bims-microg Biomed News
on Microglia in health and disease
Issue of 2024–09–08
43 papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Microglial PCGF1 alleviates neuroinflammation associated depressive behavior in adolescent mice.
  2. Decreased sialylation elicits complement-related microglia response and bipolar cell loss in the mouse retina.
  3. Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer's disease.
  4. Complement 3a induces the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms during the development and progression of Alzheimer's disease.
  5. Galectin-9 Mediates the Functions of Microglia in the Hypoxic Brain Tumor Microenvironment.
  6. IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease.
  7. Neuronal and glial cell alterations involved in the retinal degeneration of the familial dysautonomia optic neuropathy.
  8. Microglia depletion and repopulation do not alter the effects of cranial irradiation on hippocampal neurogenesis.
  9. Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response.
  10. Single-cell RNA sequencing integrated with bulk RNA sequencing analysis reveals the protective effects of lactate-mediated lactylation of microglia-related proteins on spinal cord injury.
  11. Blockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer's disease pathologies.
  12. Quercetin protects against sepsis-associated encephalopathy by inhibiting microglia-neuron crosstalk via the CXCL2/CXCR2 signaling pathway.
  13. Tyrosine phosphorylation and palmitoylation of TRPV2 ion channel tune microglial beta-amyloid peptide phagocytosis.
  14. Oxysterol Induces Expression of 60 kDa Chaperone Protein on Cell Surface of Microglia.
  15. Small Molecule Decoy of Amyloid-β Aggregation Blocks Activation of Microglia-Like Cells.
  16. Photoreceptor regeneration occurs normally in microglia-deficient irf8 mutant zebrafish following acute retinal damage.
  17. Piezo1 activation on microglial cells exacerbates demyelination in sepsis by influencing the CCL25/GRP78 pathway.
  18. Impact of sympathetic hyperactivity induced by brain microglial activation on organ damage in sepsis with chronic kidney disease.
  19. Microglia synchronizes with the circadian rhythm of the glymphatic system and modulates glymphatic system function.
  20. Inhibiting the NF-κB/DRP1 Axis Affords Neuroprotection after Spinal Cord Injury via Inhibiting Polarization of Pro-Inflammatory Microglia.
  21. Dynamic changes in pyroptosis following spinal cord injury and the identification of crucial molecular signatures through machine learning and single-cell sequencing.
  22. IL-33 relieves nerve injury by mediating microglial polarization in neuromyelitis optica spectrum disorders via the IL-33/ST2 pathway.
  23. Nicotinamide mononucleotide mitigates neuroinflammation by enhancing GPX4-mediated ferroptosis defense in microglia.
  24. Hidden role of microglia during neurodegenerative disorders and neurocritical care: A mitochondrial perspective.
  25. Single-cell sequencing reveals glial cell involvement in development of neuropathic pain via myelin sheath lesion formation in the spinal cord.
  26. Suppression of the JAK/STAT pathway inhibits neuroinflammation in the line 61-PFF mouse model of Parkinson's disease.
  27. Variant-to-function mapping of late-onset Alzheimer's disease GWAS signals in human microglial cell models implicates RTFDC1 at the CASS4 locus.
  28. Microglia LILRB4 upregulation reduces brain damage after acute ischemic stroke by limiting CD8+ T cell recruitment.
  29. Interpretation of Neurodegenerative GWAS Risk Alleles in Microglia and their Interplay with Other Cell Types.
  30. Visualization, Fate Mapping, Ablation, and Mutagenesis of Microglia in the Mouse Brain.
  31. Deciphering glial contributions to CSF1R-related disorder via single-nuclear transcriptomic profiling: a case study.
  32. Loss of Insulin Signaling in Microglia Impairs Cellular Uptake of Aβ and Neuroinflammatory Response Exacerbating Alzheimer-like Neuropathology.
  33. Early life psychosocial stress increases binge-like ethanol consumption and CSF1R inhibition prevents stress-induced alterations in microglia and brain macrophage population density.
  34. Progress in Structural and Functional In Vivo Imaging of Microglia and Their Application in Health and Disease.
  35. Microglia morphology in the developing primate amygdala and effects of early life stress.
  36. Microglia in Neuropathic Pain.
  37. Emerging Models to Study Human Microglia In vitro.
  38. Metabolic Control of Microglia.
  39. Stress and Microglia: A Double-edged Relationship.
  40. Aging Microglia and Their Impact in the Nervous System.
  41. Contactomics of Microglia and Intercellular Communication.
  42. Microglial Positron Emission Tomography Imaging In Vivo : Positron Emission Tomography Radioligands: Utility in Research and Clinical Practice.
  43. Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States.
  1. Mol Psychiatry. 2024 Aug 30.
    Microglial PCGF1 alleviates neuroinflammation associated depressive behavior in adolescent mice.
    Naigang Li, Jingyi Du, Ying Yang, Tiantian Zhao, Dong Wu, Fan Peng, Dongshuang Wang, Linghua Kong, Wenjuan Zhou, Aijun Hao.
      Epigenetics plays a crucial role in regulating gene expression during adolescent brain maturation. In adolescents with depression, microglia-mediated chronic neuroinflammation may contribute to the activation of cellular signaling cascades and cause central synapse loss. However, the exact mechanisms underlying the epigenetic regulation of neuroinflammation leading to adolescent depression remain unclear. In this study, we found that the expression of polycomb group 1 (PCGF1), an important epigenetic regulator, was decreased both in the plasma of adolescent major depressive disorder (MDD) patients and in the microglia of adolescent mice in a mouse model of depression. We demonstrated that PCGF1 alleviates neuroinflammation mediated by microglia in vivo and in vitro, reducing neuronal damage and improving depression-like behavior in adolescent mice. Mechanistically, PCGF1 inhibits the transcription of MMP10 by upregulating RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, specifically inhibiting microglia-mediated neuroinflammation. These results provide valuable insights into the pathogenesis of adolescent depression, highlighting potential links between histone modifications, neuroinflammation and nerve damage. Potential mechanisms of microglial PCGF1 regulates depression-like behavior in adolescent mice. Microglial PCGF1 inhibits NF-κB/MAPK pathway activation through regulation of RING1B/H2AK119ub and EZH2/H3K27me3 in the MMP10 promoter region, which attenuates neuroinflammation and ameliorates depression-like behaviors in adolescent mice.
    DOI:  https://doi.org/10.1038/s41380-024-02714-2
  2. Glia. 2024 Sep 03.
    Decreased sialylation elicits complement-related microglia response and bipolar cell loss in the mouse retina.
    German Cuevas-Rios, Tawfik Abou Assale, Jannis Wissfeld, Annemarie Bungartz, Julia Hofmann, Thomas Langmann, Harald Neumann.
      Sialylation plays an important role in self-recognition, as well as keeping the complement and innate immune systems in check. It is unclear whether the reduced sialylation seen during aging and in mice heterozygous for the null mutant of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (Gne+/-), an essential enzyme for sialic acid biosynthesis, contributes to retinal inflammation and degeneration. We found a reduction of polysialic acid and trisialic acid expression in several retinal layers in Gne+/- mice at 9 months of age compared to Gne+/+ wildtype (WT) mice, which was associated with a higher microglial expression of the lysosomal marker CD68. Furthermore, the total number of rod bipolar cells was reduced in 12 months old Gne+/- mice in comparison to WT mice, demonstrating loss of these retinal interneurons. Transcriptome analysis showed up-regulation of complement, inflammation, and apoptosis-related pathways in the retinas of Gne+/- mice. Particularly, increased gene transcript levels of the complement factors C3 and C4 and the pro-inflammatory cytokine Il-1β were observed by semi-quantitative real-time polymerase chain reaction (sqRT-PCR) in 9 months old Gne+/- mice compared to WT mice. The increased expression of CD68, loss of rod bipolar cells, and increased gene transcription of complement factor C4, were all prevented after crossing Gne+/- mice with complement factor C3-deficient animals. In conclusion, our data show that retinal hyposialylation in 9 and 12 months old Gne+/- mice was associated with complement-related inflammation and lysosomal microglia response, as well as rod bipolar cells loss, which was absent after genetic deletion of complement factor C3.
    Keywords:  bipolar cells; complement; inflammation; microglia; retina; sialic acid; sialylation
    DOI:  https://doi.org/10.1002/glia.24613
  3. Mol Neurodegener. 2024 Sep 05. 19(1): 64
    Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer's disease.
    Artem Zatcepin, Johannes Gnörich, Boris-Stephan Rauchmann, Laura M Bartos, Stephan Wagner, Nicolai Franzmeier, Maura Malpetti, Xianyuan Xiang, Yuan Shi, Samira Parhizkar, Maximilian Grosch, Karin Wind-Mark, Sebastian T Kunte, Leonie Beyer, Carolin Meyer, Desirée Brösamle, Ann-Christin Wendeln, Collins Osei-Sarpong, Steffanie Heindl, Arthur Liesz, Sophia Stoecklein, Gloria Biechele, Anika Finze, Florian Eckenweber, Simon Lindner, Axel Rominger, Peter Bartenstein, Michael Willem, Sabina Tahirovic, Jochen Herms, Katharina Buerger, Mikael Simons, Christian Haass, Rainer Rupprecht, Markus J Riemenschneider, Nathalie L Albert, Marc Beyer, Jonas J Neher, Lars Paeger, Johannes Levin, Günter U Höglinger, Robert Perneczky, Sibylle I Ziegler, Matthias Brendel.
       BACKGROUND: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker.
    METHODS: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization.
    RESULTS: Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia.
    CONCLUSION: Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.
    Keywords:  Alzheimer’s disease; Brain connectivity; Dementia; Microglia; Microglia desynchronization; Microglia synchronicity; Neuroinflammation; PET; TSPO
    DOI:  https://doi.org/10.1186/s13024-024-00752-6
  4. Neurosci Biobehav Rev. 2024 Aug 30. pii: S0149-7634(24)00337-3. [Epub ahead of print]165 105868
    Complement 3a induces the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms during the development and progression of Alzheimer's disease.
    Tong-Qi Ge, Pei-Pei Guan, Pu Wang.
      As a central molecule in complement system (CS), complement (C) 3 is upregulated in the patients and animal models of Alzheimer's disease (AD). C3 will metabolize to iC3b and C3a. iC3b is responsible for clearing β-amyloid protein (Aβ). In this scenario, C3 exerts neuroprotective effects against the disease via iC3b. However, C3a will inhibit microglia to clear the Aβ, leading to the deposition of Aβ and impair the functions of synapses. To their effects on AD, activation of C3a and C3a receptor (C3aR) will impair the mitochondria, leading to the release of reactive oxygen species (ROS), which activates the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes. The overloading of NLRP3 inflammasomes activate microglia, leading to the formation of inflammatory environment. The inflammatory environment will facilitate the deposition of Aβ and abnormal synapse pruning, which results in the progression of AD. Therefore, the current review will decipher the mechanisms of C3a inducing the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms, which facilitates the understanding the AD.
    Keywords:  Alzheimer’s disease; C3a receptor; Complement 3a; Microglia; Mitochondria; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.neubiorev.2024.105868
  5. Cancer Res. 2024 Aug 29.
    Galectin-9 Mediates the Functions of Microglia in the Hypoxic Brain Tumor Microenvironment.
    Chanju Lee, Dahee Yu, Hyung-Seok Kim, Ki Sun Kim, Chi Young Chang, Hee Jung Yoon, Su Bin Won, Dae Yeon Kim, Eun Ah Goh, Yong Sun Lee, Jong Bae Park, Sang Soo Kim, Eun Jung Park.
      Galectin-9 is a multifaceted regulator of various pathophysiological processes that exerts positive or negative effects in a context-dependent manner. Here, we elucidated the distinctive functional properties of galectin-9 on myeloid cells within the brain tumor microenvironment. Galectin-9-expressing cells were abundant at the hypoxic tumor edge in the tumor-bearing ipsilateral hemisphere compared to the contralateral hemisphere in an intracranial mouse brain tumor model. Galectin-9 was highly expressed in microglia and macrophages in tumor-infiltrating cells. In primary glia, both the expression and secretion of galectin-9 were influenced by tumors. Analysis of a human glioblastoma bulk RNA-sequencing dataset and a single-cell RNA-sequencing dataset from a murine glioma model revealed a correlation between galectin-9 expression and glial cell activation. Notably, the galectin-9high microglial subset was functionally distinct from the galectin-9neg/low subset in the brain tumor microenvironment. Galectin-9high microglia exhibited properties of inflammatory activation and higher rates of cell death, whereas galectin-9neg/low microglia displayed a superior phagocytic ability against brain tumor cells. Blockade of galectin-9 suppressed tumor growth and altered the activity of glial and T cells in a mouse glioma model. Additionally, glial galectin-9 expression was regulated by Hif-2α in the hypoxic brain tumor microenvironment. Myeloid-specific Hif-2α deficiency led to attenuated tumor progression. Together, these findings reveal that galectin-9 on myeloid cells is an immunoregulator and putative therapeutic target in brain tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3878
  6. J Neuroinflammation. 2024 Aug 30. 21(1): 212
    IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease.
    Radhika Joshi, Veronika Brezani, Gabrielle M Mey, Sergi Guixé-Muntet, Marti Ortega-Ribera, Yuan Zhuang, Adam Zivny, Sebastian Werneburg, Jordi Gracia-Sancho, Gyongyi Szabo.
      The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D: IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimer's disease, notably apolipoprotein-e. Using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 (ZBP1) as a target of IRF3 that is relevant across various neuroinflammatory disorders. Lastly, we show IRF3 phosphorylation and IRF3-dependent ZBP1 induction in response to Aβ in primary microglia cultures. Together, our results identify IRF3 as an important regulator of LPS and Aβ -mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases.
    Keywords:  APOE; ARM; Alzheimer’s disease; Amyloid beta; DAM; IRF3; IRM; Neuroinflammation; Type 1 interferon; ZBP1
    DOI:  https://doi.org/10.1186/s12974-024-03203-7
  7. Glia. 2024 Sep 03.
    Neuronal and glial cell alterations involved in the retinal degeneration of the familial dysautonomia optic neuropathy.
    Anastasia Schultz, Henar Albertos-Arranz, Xavier Sánchez Sáez, Jamie Morgan, Diane C Darland, Alejandra Gonzalez-Duarte, Horacio Kaufmann, Carlos E Mendoza-Santiesteban, Nicolás Cuenca, Frances Lefcort.
      Familial dysautonomia (FD) is a rare genetic neurodevelopmental and neurodegenerative disorder. In addition to the autonomic and peripheral sensory neuropathies that challenge patient survival, one of the most debilitating symptoms affecting patients' quality of life is progressive blindness resulting from the steady loss of retinal ganglion cells (RGCs). Within the FD community, there is a concerted effort to develop treatments to prevent the loss of RGCs. However, the mechanisms underlying the death of RGCs are not well understood. To study the mechanisms underlying RGC death, Pax6-cre;Elp1loxp/loxp male and female mice and postmortem retinal tissue from an FD patient were used to explore the neuronal and non-neuronal cellular pathology associated with the FD optic neuropathy. Neurons, astrocytes, microglia, Müller glia, and endothelial cells were investigated using a combination of histological analyses. We identified a novel disruption of cellular homeostasis and gliosis in the FD retina. Beginning shortly after birth and progressing with age, the FD retina is marked by astrogliosis and perturbations in microglia, which coincide with vascular remodeling. These changes begin before the onset of RGC death, suggesting alterations in the retinal neurovascular unit may contribute to and exacerbate RGC death. We reveal for the first time that the FD retina pathology includes reactive gliosis, increased microglial recruitment to the ganglion cell layer (GCL), disruptions in the deep and superficial vascular plexuses, and alterations in signaling pathways. These studies implicate the neurovascular unit as a disease-modifying target for therapeutic interventions in FD.
    Keywords:  cell stress; familial dysautonomia; neurovascular unit; optic neuropathy; retina; retinal ganglion cells
    DOI:  https://doi.org/10.1002/glia.24612
  8. Brain Behav Immun. 2024 Aug 30. pii: S0889-1591(24)00576-2. [Epub ahead of print]
    Microglia depletion and repopulation do not alter the effects of cranial irradiation on hippocampal neurogenesis.
    Kai Zhou, Georgios Alkis Zisiadis, Monique Havermans, Adamantia Fragkopoulou, Cecilia Dominguez, Makiko Ohshima, Ahmed M Osman, Carlos F D Rodrigues, Klas Blomgren.
      Cranial radiotherapy can cause lifelong cognitive complications in childhood brain tumor survivors, and reduced hippocampal neurogenesis is hypothesized to contribute to this. Following irradiation (IR), microglia clear dead neural progenitors and give rise to a neuroinflammatory microenvironment, which promotes a switch in surviving progenitors from neuronal to glial differentiation. Recently, depletion and repopulation of microglia were shown to promote neurogenesis and ameliorate cognitive deficits in various brain injury models. In this study, we utilized the Cx3cr1CreERt2-YFP/+Rosa26DTA/+ transgenic mouse model to deplete microglia in the juvenile mouse brain before subjecting them to whole-brain IR and investigated the short- and long-term effects on hippocampal neurogenesis. Within the initial 24 h after IR, the absence of microglia led to an accumulation of dead cells in the subgranular zone, and 50-fold higher levels of the chemokine C-C motif ligand 2 (CCL2), in sham brains and 7-fold higher levels after IR. The absence of microglia, and the subsequent repopulation within 10 days, did neither affect the loss of proliferating or doublecortin-positive cells, nor the reduced growth of the granule cell layer. Our results argue against a role for a pro-inflammatory microenvironment in the dysregulation of hippocampal neurogenesis and suggest that the observed reduction of neurogenesis was solely due to IR.
    Keywords:  Apoptosis; CCL2; Doublecortin; Late complications; Microglia depletion; Microglia repopulation; Neuroinflammation; Phagocytosis
    DOI:  https://doi.org/10.1016/j.bbi.2024.08.055
  9. Cell Death Dis. 2024 Aug 27. 15(8): 625
    Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response.
    Juan García-Revilla, Rocío Ruiz, Ana M Espinosa-Oliva, Marti Santiago, Irene García-Domínguez, Lluís Camprubí-Ferrer, Sara Bachiller, Tomas Deierborg, Bertrand Joseph, Rocío M de Pablos, José A Rodríguez-Gómez, José Luis Venero.
      Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc). Apoptosis is thought to play a critical role in the progression of PD, and thus understanding the effects of antiapoptotic strategies is crucial for developing potential therapies. In this study, we developed a unique genetic model to selectively delete Casp3, the gene encoding the apoptotic protein caspase-3, in dopaminergic neurons (TH-C3KO) and investigated its effects in response to a subacute regime of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, which is known to trigger apoptotic loss of SNpc dopaminergic neurons. We found that Casp3 deletion did not protect the dopaminergic system in the long term. Instead, we observed a switch in the cell death pathway from apoptosis in wild-type mice to necrosis in TH-C3KO mice. Notably, we did not find any evidence of necroptosis in our model or in in vitro experiments using primary dopaminergic cultures exposed to 1-methyl-4-phenylpyridinium in the presence of pan-caspase/caspase-8 inhibitors. Furthermore, we detected an exacerbated microglial response in the ventral mesencephalon of TH-C3KO mice in response to MPTP, which mimicked the microglia neurodegenerative phenotype (MGnD). Under these conditions, it was evident the presence of numerous microglial phagocytic cups wrapping around apparently viable dopaminergic cell bodies that were inherently associated with galectin-3 expression. We provide evidence that microglia exhibit phagocytic activity towards both dead and stressed viable dopaminergic neurons through a galectin-3-dependent mechanism. Overall, our findings suggest that inhibiting apoptosis is not a beneficial strategy for treating PD. Instead, targeting galectin-3 and modulating microglial response may be more promising approaches for slowing PD progression.
    DOI:  https://doi.org/10.1038/s41419-024-07014-9
  10. CNS Neurosci Ther. 2024 Sep;30(9): e70028
    Single-cell RNA sequencing integrated with bulk RNA sequencing analysis reveals the protective effects of lactate-mediated lactylation of microglia-related proteins on spinal cord injury.
    Bin Zhang, Fudong Li, Yangyang Shi, Chenglong Ji, Qingjie Kong, Kaiqiang Sun, Xiaofei Sun.
       BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) results in significant neurological deficits, and microglia play the critical role in regulating the immune microenvironment and neurological recovery. Protein lactylation has been found to modulate the function of immune cells. Therefore, this study aimed to elucidate the effects of glycolysis-derived lactate on microglial function and its potential neuroprotective mechanisms via lactylation after SCI.
    METHODS: Single-cell RNA sequencing (scRNA-seq) data were obtained from figshare to analyze cellular and molecular alterations within the spinal cord post-SCI, further focusing on the expression of microglia-related genes for cell sub-clustering, trajectory analysis, and glycolysis function analysis. We also evaluated the expression of lactylation-related genes in microglia between day 7 after SCI and sham group. Additionally, we established the mice SCI model and performed the bulk RNA sequencing in a time-dependent manner. The expression of glycolysis- and lactylation-related genes was evaluated, as well as the immune infiltration analysis based on the lactylation-related genes. Then, we investigated the bio-effects of lactate on the inflammation and polarization phenotype of microglia. Finally, adult male C57BL/6 mice were subjected to exercise first to increase lactate level, before SCI surgery, aiming to evaluate the protective effects of lactate-mediated lactylation of microglia-related proteins on SCI.
    RESULTS: scRNA-seq identified a subcluster of microglia, recombinant chemokine C-X3-C-motif receptor 1+ (CX3CR1+) microglia, which is featured by M1-like phenotype and increased after SCI. KEGG analysis revealed the dysfunctional glycolysis in microglia after SCI surgery, and AUCell analysis suggested that the decreased glycolysis an increased oxidative phosphorylation in CX3CR1+ microglia. Differential gene analysis suggested that several lactylation-related genes (Fabp5, Lgals1, Vim, and Nefl) were downregulated in CX3CR1+ microglia at day 7 after SCI, further validated by the results from bulk RNA sequencing. Immunofluorescence staining indicated the expression of lactate dehydrogenase A (LDHA) in CX3CR1+ microglia also decreased at day 7 after SCI. Cellular experiments demonstrated that the administration of lactate could increase the lactylation level and inhibit the pro-inflammatory phenotype in microglia. Functionally, exercise-mediated lactate production resulted in improved locomotor recovery and decreased inflammatory markers in SCI mice compared to SCI alone.
    CONCLUSIONS: In the subacute phase of SCI, metabolic remodeling in microglia may be key therapeutic targets to promote nerve regeneration, and lactate contributed to neuroprotection after SCI by influencing microglial lactylation and inflammatory phenotype, which offered a novel approach for therapeutic intervention.
    Keywords:  Lactylation; glycolysis; lactate; microglial polarization; neuroinflammation; spinal cord injury
    DOI:  https://doi.org/10.1111/cns.70028
  11. Exp Mol Med. 2024 Sep 02.
    Blockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer's disease pathologies.
    Sunwoo Chung, June-Hyun Jeong, Jong-Chan Park, Jong Won Han, Yeajina Lee, Jong-Il Kim, Inhee Mook-Jung.
      Abnormal glial activation promotes neurodegeneration in Alzheimer's disease (AD), the most common cause of dementia. Stimulation of the cGAS-STING pathway induces microglial dysfunction and sterile inflammation, which exacerbates AD. We showed that inhibiting STING activation can control microglia and ameliorate a wide spectrum of AD symptoms. The cGAS-STING pathway is required for the detection of ectopic DNA and the subsequent immune response. Amyloid-β (Aβ) and tau induce mitochondrial stress, which causes DNA to be released into the cytoplasm of microglia. cGAS and STING are highly expressed in Aβ plaque-associated microglia, and neuronal STING is upregulated in the brains of AD model animals. The presence of the APOE ε4 allele, an AD risk factor, also upregulated both proteins. STING activation was necessary for microglial NLRP3 activation, proinflammatory responses, and type-I-interferon responses. Pharmacological STING inhibition reduced a wide range of AD pathogenic features in AppNL-G-F/hTau double-knock-in mice. An unanticipated transcriptome shift in microglia reduced gliosis and cerebral inflammation. Significant reductions in the Aβ load, tau phosphorylation, and microglial synapse engulfment prevented memory loss. To summarize, our study describes the pathogenic mechanism of STING activation as well as its potential as a therapeutic target in AD.
    DOI:  https://doi.org/10.1038/s12276-024-01295-y
  12. Phytomedicine. 2024 Aug 26. pii: S0944-7113(24)00645-7. [Epub ahead of print]134 155987
    Quercetin protects against sepsis-associated encephalopathy by inhibiting microglia-neuron crosstalk via the CXCL2/CXCR2 signaling pathway.
    Yu-Shen Yang, Chu-Yun Liu, Meng-Qin Pei, Zhen-Dong Sun, Shu Lin, He-Fan He.
       BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common brain lesion associated with severe sepsis, for which ferroptosis is a key driving factor. Thus, suppressing ferroptosis may be an effective strategy for treating SAE. Quercetin (QUE) is a natural flavonoid with antioxidant and anti-inflammatory properties. However, its role on ferroptosis in SAE remains unclear.
    PURPOSE: This study aimed to investigate the mechanism underlying the therapeutic effect of QUE on cecal ligation perforation (CLP)-induced SAE.
    METHODS: In vivo and in vitro SAE models were established using CLP and lipopolysaccharide (LPS), respectively. Both models underwent pre-treatment with QUE.
    RESULTS: QUE attenuated CLP-induced symptoms, including temperature changes, neurological severity scores, learning and memory dysfunction, inflammatory cytokine release, and microglia activation in SAE mice, and inhibited LPS-induced microglia recruitment and chemotaxis. Bioinformatics analysis revealed that the C-X-C motif chemokine ligand 2 (CXCL2)/C-X-C motif chemokine receptor 2 (CXCR2) axis may play a key role in QUE-mediated protection against SAE. Moreover, QUE significantly inhibited LPS-induced CXCL2 up-regulation and protein secretion from microglia. Recombinant mouse-derived CXCL2 (rmCXCL2) promoted inflammatory cytokine secretion, NF-κB/NLRP3 signaling activation, and microglia recruitment and chemotaxis. Furthermore, rmCXCL2 induced ferroptosis in mouse hippocampal neurons, as evidenced by elevated malondialdehyde levels, decreased glutathione levels, excessive iron uptake, and altered ferroptosis-related protein expression. The CXCR2 antagonist SB225002 effectively reversed the effects of rmCXCL2. Importantly, in vivo experiments further demonstrated that the therapeutic effect of QUE on SAE was inhibited by rmCXCL2.
    CONCLUSION: This study demonstrates that CXCL2 secreted by activated microglia mediates microglia self-activation and induces hippocampal neuronal ferroptosis via CXCR2 and that QUE exerts neuroprotective effects on SAE by blocking interactions between microglia and neurons via CXCL2/CXCR2 pathway inhibition.
    Keywords:  CXCL2/CXCR2 pathway; Ferroptosis; Microglia-neuron interaction; Quercetin; Sepsis-associated encephalopathy
    DOI:  https://doi.org/10.1016/j.phymed.2024.155987
  13. J Neuroinflammation. 2024 Sep 03. 21(1): 218
    Tyrosine phosphorylation and palmitoylation of TRPV2 ion channel tune microglial beta-amyloid peptide phagocytosis.
    Shaobin Yang, Yaqin Du, Yanhong Li, Qi Tang, Yimeng Zhang, Xiaoqian Zhao.
      Alzheimer's disease (AD) is the leading form of dementia, characterized by the accumulation and aggregation of amyloid in brain. Transient receptor potential vanilloid 2 (TRPV2) is an ion channel involved in diverse physiopathological processes, including microglial phagocytosis. Previous studies suggested that cannabidiol (CBD), an activator of TRPV2, improves microglial amyloid-β (Aβ) phagocytosis by TRPV2 modulation. However, the molecular mechanism of TRPV2 in microglial Aβ phagocytosis remains unknown. In this study, we aimed to investigate the involvement of TRPV2 channel in microglial Aβ phagocytosis and the underlying mechanisms. Utilizing human datasets, mouse primary neuron and microglia cultures, and AD model mice, to evaluate TRPV2 expression and microglial Aβ phagocytosis in both in vivo and in vitro. TRPV2 was expressed in cortex, hippocampus, and microglia.Cannabidiol (CBD) could activate and sensitize TRPV2 channel. Short-term CBD (1 week) injection intraperitoneally (i.p.) reduced the expression of neuroinflammation and microglial phagocytic receptors, but long-term CBD (3 week) administration (i.p.) induced neuroinflammation and suppressed the expression of microglial phagocytic receptors in APP/PS1 mice. Furthermore, the hyper-sensitivity of TRPV2 channel was mediated by tyrosine phosphorylation at the molecular sites Tyr(338), Tyr(466), and Tyr(520) by protein tyrosine kinase JAK1, and these sites mutation reduced the microglial Aβ phagocytosis partially dependence on its localization. While TRPV2 was palmitoylated at Cys 277 site and blocking TRPV2 palmitoylation improved microglial Aβ phagocytosis. Moreover, it was demonstrated that TRPV2 palmitoylation was dynamically regulated by ZDHHC21. Overall, our findings elucidated the intricate interplay between TRPV2 channel regulated by tyrosine phosphorylation/dephosphorylation and cysteine palmitoylation/depalmitoylation, which had divergent effects on microglial Aβ phagocytosis. These findings provide valuable insights into the underlying mechanisms linking microglial phagocytosis and TRPV2 sensitivity, and offer potential therapeutic strategies for managing AD.
    Keywords:  Alzheimer’s disease; Microglia; Phagocytosis; Phosphorylation; Transient receptor potential vanilloid family type 2
    DOI:  https://doi.org/10.1186/s12974-024-03204-6
  14. Int J Mol Sci. 2024 Aug 21. pii: 9073. [Epub ahead of print]25(16):
    Oxysterol Induces Expression of 60 kDa Chaperone Protein on Cell Surface of Microglia.
    Koanhoi Kim, Hyok-Rae Cho, Bo-Young Kim, Jaesung Kim, Dongha Park, Ryuk Jun Kwon, Yonghae Son.
      Microglia, essential immune cells in the brain, play crucial roles in neuroinflammation by performing various functions such as neurogenesis, synaptic pruning, and pathogen defense. These cells are activated by inflammatory factors like β-amyloid (Aβ) and oxysterols, leading to morphological and functional changes, including the secretion of inflammatory cytokines and the upregulation of MHC class II molecules. This study focused on identifying specific markers for microglial activation, with a particular emphasis on the roles of oxysterols in this process. We used the HMC3 human microglial cell line to investigate the induction of heat shock protein 60 (HSP60), a chaperonin protein by oxysterols, specifically in the presence of 25-hydroxycholesterol (25OHChol) and 27-hydroxycholesterol (27OHChol). Our findings obtained by the proteomics approach revealed that these oxysterols significantly increased HSP60 expression on microglial cells. This induction was further confirmed using Western blot analysis and immunofluorescence microscopy. Additionally, Aβ1-42 also promoted HSP60 expression, indicating its role as a microglial activator. HSP60 involved in protein folding and immune modulation was identified as a potential marker for microglial activation. This study underscores the importance of HSP60 in the inflammatory response of microglia, suggesting its utility as a target for new therapeutic approaches in neuroinflammatory diseases such as Alzheimer's disease (AD).
    Keywords:  25-hydroxycholesterol; 27-hydroxycholesterol; HSP60; microglia; neuroinflammation
    DOI:  https://doi.org/10.3390/ijms25169073
  15. J Alzheimers Dis. 2024 Sep 04.
    Small Molecule Decoy of Amyloid-β Aggregation Blocks Activation of Microglia-Like Cells.
    Sho Oasa, Gefei Chen, Marianne Schultzberg, Lars Terenius.
       Background: Aggregated forms of the amyloid-β (Aβ) peptides which form protofibrils and fibrils in the brain are signatures of Alzheimer's disease (AD). Aggregates are also recognized by microglia, which in early phases maybe protective and in later phases contribute to the pathology. We have identified several small molecules, decoys which interfere with Aβ oligomerization and induce other aggregation trajectories leading to aggregated macrostructures which are non-toxic.
    Objective: This study investigates whether the small-molecule decoys affect microglial activation in terms of cytokine secretion and phagocytosis of Aβ peptide.
    Methods: The effects of the decoys (NSC 69318, NSC 100873, NSC 16224) were analyzed in a model of human THP-1 monocytes differentiated to microglia-like cells. The cells were activated by Aβ40 and Aβ42 peptides, respectively, and after treatment with each decoy the secreted levels of pro-inflammatory cytokines and the Aβ phagocytosis were analyzed.
    Results: NSC16224, which generates a double-stranded aggregate of thin protofibrils, was found to block Aβ40- and Aβ42-induced increase in microglial secretion of pro-inflammatory cytokines. NSC 69318, selective for neurotoxicity of Aβ42, and NSC 100873 did not significantly reduce the microglial activation in terms of cytokine secretion. The uptake of Aβ42 was not affected by anyone of the decoys.
    Conclusions: Our findings open the possibility that the molecular decoys of Aβ aggregation may block microglial activation by Aβ40 and Aβ42 in addition to blocking neurotoxicity as shown previously.
    Keywords:  Alzheimer’s disease; amyloid-β; cytokine; inflammation; interleukin; tumor necrosis factor
    DOI:  https://doi.org/10.3233/JAD-231399
  16. Sci Rep. 2024 08 30. 14(1): 20146
    Photoreceptor regeneration occurs normally in microglia-deficient irf8 mutant zebrafish following acute retinal damage.
    Ping Song, Dhwani Parsana, Rupesh Singh, Lana M Pollock, Bela Anand-Apte, Brian D Perkins.
      Microglia are resident immune cells in the central nervous system, including the retina that surveil the environment for damage and infection. Following retinal damage, microglia undergo morphological changes, migrate to the site of damage, and express and secrete pro-inflammatory signals. In the zebrafish retina, inflammation induces the reprogramming and proliferation of Müller glia and the regeneration of neurons following damage or injury. Immunosuppression or pharmacological ablation of microglia reduce or abolish Müller glia proliferation. We evaluated the retinal architecture and retinal regeneration in adult zebrafish irf8 mutants, which have significantly depleted numbers of microglia. We show that irf8 mutants have normal retinal structure at 3 months post fertilization (mpf) and 6 mpf but fewer cone photoreceptors by 10 mpf. Surprisingly, light-induced photoreceptor ablation induced Müller glia proliferation in irf8 mutants and cone and rod photoreceptor regeneration. Light-damaged retinas from both wild-type and irf8 mutants show upregulated expression of mmp-9, il8, and tnfβ pro-inflammatory cytokines. Our data demonstrate that adult zebrafish irf8 mutants can regenerate normally following acute retinal injury. These findings suggest that microglia may not be essential for retinal regeneration in zebrafish and that other mechanisms can compensate for the reduction in microglia numbers.
    Keywords:  Inflammation; Microglia; Müller glia; Photoreceptors; Regeneration; Retina
    DOI:  https://doi.org/10.1038/s41598-024-70859-9
  17. Int Immunopharmacol. 2024 Sep 04. pii: S1567-5769(24)01566-2. [Epub ahead of print]142(Pt A): 113045
    Piezo1 activation on microglial cells exacerbates demyelination in sepsis by influencing the CCL25/GRP78 pathway.
    Di Xie, Yanli Ma, Chengjin Gao, Shuming Pan.
       BACKGROUND: In sepsis-associated encephalopathy (SAE), the activation of microglial cells and ensuing neuroinflammation are important in the underlying pathological mechanisms. Increasing evidence suggests that the protein Piezo1 functions as a significant regulator of neuroinflammation. However, the influence of Piezo1 on microglial cells in the context of SAE has not yet been determined. This study aims to investigate the role of Piezo1 in microglial cells in the context of SAE.
    METHODS: By inducing cecal ligation and puncture (CLP), a mouse model of SAE was established, while the control group underwent a sham surgery in which the cecum was exposed without ligation and puncture. Piezo1 knockout mice were employed in this study. Morris water maze tests were conducted between Days 14 and 18 postop to assess both the motor activity and cognitive function. A proteomic analysis was conducted to assess the SAE-related pathways, whereas a Mendelian randomization analysis was conducted to identify the pathways associated with cognitive impairment. Dual-label immunofluorescence and flow cytometry were used to assess the secretion of inflammatory factors, microglial status, and oligodendrocyte development. Electron microscopy was used to evaluate axonal myelination. A western blot analysis was conducted to evaluate the influence of Piezo1 on oligodendrocyte ferroptosis.
    RESULTS: The results of the bioinformatics analysis have revealed the significant involvement of CCL25 in the onset and progression of SAE-induced cognitive impairment. SAE leads to cognitive dysfunction by activating the microglial cells. The release of CCL25 by the activated microglia initiates the demyelination of oligodendrocytes in the hippocampus, resulting in ferroptosis and the disruption of hippocampal functional connectivity. Of note, the genetic knockout of the Piezo1 gene mitigates these changes. The treatment with siRNA targeting Piezo1 effectively reduces the secretion of inflammatory mediators CCL25 and IL-18 by inhibiting the p38 pathway, thus preventing the ferroptosis of oligodendrocytes through the modulation of the CCL25/GPR78 axis.
    CONCLUSION: Piezo1 is involved in the activation of microglia and demyelinating oligodendrocytes in the animal models of SAE, resulting in cognitive impairment. Consequently, targeting Piezo1 suppression can be a promising approach for therapeutic interventions aimed at addressing cognitive dysfunction associated with SAE.
    Keywords:  CCL25; Demyelination; IL-18; Neuroinflammation; Piezo1
    DOI:  https://doi.org/10.1016/j.intimp.2024.113045
  18. J Intensive Care. 2024 Sep 02. 12(1): 31
    Impact of sympathetic hyperactivity induced by brain microglial activation on organ damage in sepsis with chronic kidney disease.
    Masaaki Nishihara, Keisuke Shinohara, Shota Ikeda, Tomohiko Akahoshi, Hiroyuki Tsutsui.
       BACKGROUND: Sympathetic nerve activity (SNA) plays a central role in the pathogenesis of several diseases such as sepsis and chronic kidney disease (CKD). Activation of microglia in the paraventricular nucleus of the hypothalamus (PVN) has been implicated in SNA. The mechanisms responsible for the adverse prognosis observed in sepsis associated with CKD remain to be determined. Therefore, we aimed to clarify the impact of increased SNA resulting from microglial activation on hemodynamics and organ damage in sepsis associated with CKD.
    METHODS AND RESULTS: In protocol 1, male Sprague-Dawley rats underwent either nephrectomy (Nx) or sham surgery followed by cecal ligation and puncture (CLP) or sham surgery. After CLP, Nx-CLP rats exhibited decreased blood pressure, increased heart rate, elevated serum creatinine and bilirubin levels, and decreased platelet count compared to Nx-Sham rats. Heart rate variability analysis revealed an increased low to high frequency (LF/HF) ratio in Nx-CLP rats, indicating increased SNA. Nx-CLP rats also had higher creatinine and bilirubin levels and lower platelet counts than sham-CLP rats after CLP. In protocol 2, Nx-CLP rats were divided into two subgroups: one received minocycline, an inhibitor of microglial activation, while the other received artificial cerebrospinal fluid (CSF) intracerebroventricularly via an osmotic minipump. The minocycline-treated group (Nx-mino-CLP) showed attenuated hypotensive and increased heart rate responses compared to the CSF-treated group (Nx-CSF-CLP), and the LF/HF ratio was also decreased. Echocardiography showed larger left ventricular dimensions and inferior vena cava in the Nx-mino-CLP group. In addition, creatinine and bilirubin levels were lower and platelet counts were higher in the Nx-mino-CLP group compared to the Nx-CSF-CLP group.
    CONCLUSIONS: In septic rats with concomitant CKD, SNA was significantly enhanced and organ dysfunction was increased. It has been suggested that the mechanism of exacerbated organ dysfunction in these models may involve abnormal systemic hemodynamics, possibly triggered by activation of the central sympathetic nervous system through activation of microglia in the PVN.
    Keywords:  Chronic kidney disease; Microglia; Paraventricular nucleus of the hypothalamus; Sepsis; Sympathetic nerve activity
    DOI:  https://doi.org/10.1186/s40560-024-00742-2
  19. IUBMB Life. 2024 Sep 02.
    Microglia synchronizes with the circadian rhythm of the glymphatic system and modulates glymphatic system function.
    Ting Yang, Yan Tang, Xinghua Liu, Song Gong, Ensheng Yao.
      Microglia, as immune cells in the central nervous system, possess the ability to adapt morphologically and functionally to their environment. Glymphatic system, the principal waste clearance system in the brain, exhibits circadian rhythms. However, the impact of microglia on the glymphatic system function remains unknown. In this study, we explored the intricate relationship between microglia and the glymphatic system. Examining diurnal patterns, we identified synchronized behaviors in glymphatic activity and microglial morphology, peaking during sleep and exhibiting distinct changes in branching complexity. Depleting microglia using PLX5622 or in P2Y12 knockout mice enhanced glymphatic function. Chemogenetic manipulation of microglia demonstrated that activating HM3D improved glymphatic function, while inhibiting HM4D unexpectedly increased microglial complexity. These findings highlight the dynamic influence of microglia on the glymphatic system.
    Keywords:  P2Y12; chemogenetics; circadian rhythms; glymphatic system; microglia
    DOI:  https://doi.org/10.1002/iub.2903
  20. Front Biosci (Landmark Ed). 2024 Aug 23. 29(8): 307
    Inhibiting the NF-κB/DRP1 Axis Affords Neuroprotection after Spinal Cord Injury via Inhibiting Polarization of Pro-Inflammatory Microglia.
    Chen Song, Kaihui Zhang, Cheng Luo, Xiaoyong Zhao, Baoshan Xu.
       BACKGROUND: Spinal cord injury (SCI) is considered a central nervous system (CNS) disorder. Nuclear factor kappa B (NF-κB) regulates inflammatory responses in the CNS and is implicated in SCI pathogenesis. The mechanism(s) through which NF-κB contributes to the neuroinflammation observed during SCI however remains unclear.
    METHODS: SCI rat models were created using the weight drop method and separated into Sham, SCI and SCI+NF-κB inhibitor groups (n = 6 rats per-group). We used Hematoxylin-Eosin Staining (H&E) and Nissl staining for detecting histological changes in the spinal cord. Basso-Beattie-Bresnahan (BBB) behavioral scores were utilized for assessing functional locomotion recovery. Mouse BV2 microglia were exposed to lipopolysaccharide (LPS) to mimic SCI-induced microglial inflammation in vitro.
    RESULTS: Inhibition of NF-κB using JSH-23 alleviated inflammation and neuronal injury in SCI rats' spinal cords, leading to improved locomotion recovery (p < 0.05). NF-κB inhibition reduced expression levels of CD86, interleukin-6 (IL-6), IL-1β, and inducible Nitric Oxide Synthase (iNOS), and improved expression levels of CD206, IL-4, and tissue growth factor-beta (TGF-β) in both LPS-treated microglia and SCI rats' spinal cords (p < 0.05). Inhibition of NF-κB also effectively suppressed mitochondrial fission, evidenced by the reduced phosphorylation of dynamin-related protein 1 (DRP1) at Ser616 (p < 0.001).
    CONCLUSION: We show that inhibition of the NF-κB/DRP1 axis prevents mitochondrial fission and suppresses pro-inflammatory microglia polarization, promoting neurological recovery in SCI. Targeting the NF-κB/DRP1 axis therefore represents a novel approach for SCI.
    Keywords:  dynamin-related protein 1; microglia polarization; mitochondrial fission; nuclear factor kappa B; spinal cord injury
    DOI:  https://doi.org/10.31083/j.fbl2908307
  21. J Pharm Biomed Anal. 2024 Aug 26. pii: S0731-7085(24)00489-8. [Epub ahead of print]251 116449
    Dynamic changes in pyroptosis following spinal cord injury and the identification of crucial molecular signatures through machine learning and single-cell sequencing.
    Chuang Li, Qingyang Li, Ruizhi Jiang, Chi Zhang, Enlin Qi, Mingxin Wu, Mingzhe Zhang, Hua Zhao, Fenge Zhao, Hengxing Zhou.
      The pathological cascade of spinal cord injury (SCI) is highly intricate. The onset of neuroinflammation can exacerbate the extent of damage. Pyroptosis is a form of inflammation-linked programmed cell death (PCD), the inhibition of pyroptosis can partially mitigate neuroinflammation. It is imperative to delineate the principal cell types susceptible to pyroptosis and concomitantly identify key genes associated with this process. We initially defined the pyroptosis-related genes (PRGs) and analyzed their expression at different time points post SCI. The results demonstrate a substantial upregulation of differentially expressed genes (DEGs) related to pyroptosis on the 7 days post-injury (dpi), these DEGs in the 7 dpi are closely related to the inflammatory response. Subsequently, immune infiltration analysis revealed a predominant presence of inflammatory microglia. Through correlation analysis, we postulated that pyroptosis primarily manifested within the inflammatory microglia. Employing machine learning algorithms, we identified four pyroptosis-related molecular signatures, which were experimentally validated using BV2 cells and spinal cord tissue samples. The robustness of the identified molecular signatures was further confirmed through single-cell sequencing data analysis. Overall, our study elucidates the temporal dynamics of pyroptosis and identifies key molecular signatures following SCI. These findings can provide novel evidence for therapeutic interventions in SCI.
    Keywords:  Machine learning; Microglia; Pyroptosis; Single-cell sequencing; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.jpba.2024.116449
  22. IBRO Neurosci Rep. 2024 Dec;17 177-187
    IL-33 relieves nerve injury by mediating microglial polarization in neuromyelitis optica spectrum disorders via the IL-33/ST2 pathway.
    Lu Huang, Congcong Fu, Sha Liao, Youming Long.
      Interleukin-33 (IL-33) is a member of the interleukin-1 cytokine family. Its function in regulating microglial M1/M2 polarization in neuromyelitis optica spectrum disorder (NMOSD) is still unelucidated. To evaluate the role of IL-33 in NMOSD, we constructed NMOSD mice model by injecting purified serum IgG from AQP4-IgG seropositive NMOSD patients into experimental autoimmune encephalomyelitis (EAE) mice, and IL-33 was intraperitoneally injected into NMOSD mice 3 d before the model induction. We found that pretreatment of the NMOSD mice with IL-33 relieved brain neuron loss, and demyelination and improved the structure of axons, astrocytes, and mitochondria. In the neuronal and microglial coculture system, pretreatment with IL-33 in microglia alleviated NMOSD serum-induced inflammation and damaged morphology in cultured neurons. IL-33 transformed microglia to the M2 phenotype, and NMOSD serum promoted microglia to the M1 phenotype in cultured BV2 cells. Moreover, IL-33 influenced microglial polarity via the IL-33/ST2 pathway. IL-33 may be a novel insight useful for further developing NMOSD-targeted therapy and drug development.
    Keywords:  AQP4; IL-33; Microglia; NMOSD; ST2
    DOI:  https://doi.org/10.1016/j.ibneur.2024.07.008
  23. Brain Res. 2024 Aug 30. pii: S0006-8993(24)00451-7. [Epub ahead of print]1845 149197
    Nicotinamide mononucleotide mitigates neuroinflammation by enhancing GPX4-mediated ferroptosis defense in microglia.
    Ruiqiong Su, Xiaoyue Pan, Qiuyuan Chen, Junyan Wang, Xuerui Kong, Yunhong Li, Huan Liu, Xiaolin Hou, Yin Wang.
       BACKGROUND: Numerous neurological diseases involving neuroinflammation, particularly microglia, contribute to neuronal death. Ferroptosis is implicated in various diseases characterized by neuronal injury. Studies showed that nicotinamide mononucleotide (NMN) inhibits both neuroinflammation and ferroptosis. However, the mechanisms of NMN in both ferroptosis and neuroinflammation remain unclear. We aimed to explore the effects of NMN on neuroinflammation and the susceptibility of microglia to ferroptosis.
    METHODS: Ferroptosis markers in macroglia exposed to lipopolysaccharides (LPS) were analyzed using CCK8, flow cytometry, ELISA, and quantitative RT-PCR. The effects of NMN on LPS-induced ferroptosis in microglia were evaluated through flow cytometry, western blot, and immunofluorescence staining. RT-PCR analysis assessed the inflammatory cytokine production of microglia subjected to Ferrostatin-1-regulated ferroptosis. RNA sequencing elucidated the underlying mechanism of NMN-involved microglia ferroptosis under LPS induction. In BV2 microglia, an inhibitor of GPX4, RSL3, was employed to suppress GPX4 expression. Intracerebroventricular injection of LPS was performed to evaluate neuroinflammation and microglia activation in vivo.
    RESULTS: NMN effectively rescued LPS-induced ferroptosis and improved cell viability in microglia. Co-administration of NMN and ferrostatin-1 significantly reduced proinflammatory cytokine production in microglia following the introduction of LPS stimuli. Mechanistically, NMN facilitated glutathione (GSH) production, and enhanced resistance to lipid peroxidation occurred in a manner dependent on GPX4, repressing cytokine transcription and protecting cells from ferroptosis. RNA sequencing elucidated the underlying mechanism of NMN-associated microglia ferroptosis under LPS induction. Furthermore, simultaneous injection of NMN ameliorated LPS-induced ferroptosis and neuroinflammation in mouse brains. The data from the present study indicated that NMN enhances GPX4-mediated ferroptosis defense against LPS-induced ferroptosis in microglia by recruiting GSH, thereby inhibiting neuroinflammation.
    CONCLUSION: Therapeutic approaches to effectively target ferroptosis in diseases using NMN, consideration should be given to both its anti-ferroptosis and anti-inflammatory effects to attain optimal outcomes, presenting promising strategies for treating neuroinflammation-related diseases or disorders.
    Keywords:  (1S,3R)-RSL3; Ferroptosis; Ferrostatin-1; Lipopolysaccharide; Microglia; Neuroinflammation; Nicotinamide mononucleotide
    DOI:  https://doi.org/10.1016/j.brainres.2024.149197
  24. Int Immunopharmacol. 2024 Aug 31. pii: S1567-5769(24)01545-5. [Epub ahead of print]142(Pt A): 113024
    Hidden role of microglia during neurodegenerative disorders and neurocritical care: A mitochondrial perspective.
    Xinrun Wang, Jiyun Hu, Shucai Xie, Wenchao Li, Haisong Zhang, Li Huang, Zhaoxin Qian, Chunguang Zhao, Lina Zhang.
      The incidence of aging-related neurodegenerative disorders and neurocritical care diseases is increasing worldwide. Microglia, the main inflammatory cells in the brain, could be potential viable therapeutic targets for treating neurological diseases. Interestingly, mitochondrial functions, including energy metabolism, mitophagy and transfer, fission and fusion, and mitochondrial DNA expression, also change in activated microglia. Notably, mitochondria play an active and important role in the pathophysiology of neurodegenerative disorders and neurocritical care diseases. This review briefly summarizes the current knowledge on mitochondrial dysfunction in microglia in neurodegenerative disorders and neurocritical care diseases and comprehensively discusses the prospects of the application of neurological injury prevention and treatment targets by mitochondria.
    Keywords:  Energy metabolism; Microglia; Mitochondrial; Mitophagy; Neurocritical care; Neurodegenerative disorders
    DOI:  https://doi.org/10.1016/j.intimp.2024.113024
  25. J Neuroinflammation. 2024 Aug 31. 21(1): 213
    Single-cell sequencing reveals glial cell involvement in development of neuropathic pain via myelin sheath lesion formation in the spinal cord.
    Danyang Li, Kaihong Yang, Jinlu Li, Xiaoqian Xu, Lanlan Gong, Shouwei Yue, Hui Wei, Zhenyu Yue, Yikun Wu, Sen Yin.
       BACKGROUND: Neuropathic pain (NP), which results from injury or lesion of the somatosensory nervous system, is intimately associated with glial cells. The roles of microglia and astrocytes in NP have been broadly described, while studies on oligodendrocytes have largely focused on axonal myelination. The mechanisms of oligodendrocytes and their interactions with other glial cells in NP development remain uncertain.
    METHODS: To explore the function of the interaction of the three glial cells and their interactions on myelin development in NP, we evaluated changes in NP and myelin morphology after a chronic constriction injury (CCI) model in mice, and used single-cell sequencing to reveal the subpopulations characteristics of oligodendrocytes, microglia, and astrocytes in the spinal cord tissues, as well as their relationship with myelin lesions; the proliferation and differentiation trajectories of oligodendrocyte subpopulations were also revealed using pseudotime cell trajectory and RNA velocity analysis. In addition, we identified chemokine ligand-receptor pairs between glial cells by cellular communication and verified them using immunofluorescence.
    RESULTS: Our study showed that NP peaked on day 7 after CCI in mice, a time at which myelin lesions were present in both the spinal cord and sciatic nerve. Oligodendrocytes, microglia, and astrocytes subpopulations in spinal cord tissue were heterogeneous after CCI and all were involved in suppressing the process of immune defense and myelin production. In addition, the differentiation trajectory of oligodendrocytes involved a unidirectional lattice process of OPC-1-Oligo-9, which was arrested at the Oligo-2 stage under the influence of microglia and astrocytes. And the CADM1-CADM1, NRP1-VEGFA interactions between glial cells are enhanced after CCI and they had a key role in myelin lesions and demyelination.
    CONCLUSIONS: Our study reveals the close relationship between the differentiation block of oligodendrocytes after CCI and their interaction with microglia and astrocytes-mediated myelin lesions and NP. CADM1/CADM1 and NRP-1/VEGFA may serve as potential therapeutic targets for use in the treatment of NP.
    Keywords:  Intercellular communication; Myelin lesion; Neuroglia; Neuropathic pain; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1186/s12974-024-03207-3
  26. J Neuroinflammation. 2024 Sep 01. 21(1): 216
    Suppression of the JAK/STAT pathway inhibits neuroinflammation in the line 61-PFF mouse model of Parkinson's disease.
    Huixian Hong, Yong Wang, Marissa Menard, Jessica A Buckley, Lianna Zhou, Laura Volpicelli-Daley, David G Standaert, Hongwei Qin, Etty N Benveniste.
      Parkinson's disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of α-synuclein (α-Syn) into insoluble aggregates called Lewy pathology. The Line 61 α-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human α-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human α-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-α-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-α-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.
    Keywords:  AZD1480; JAK/STAT; Neuroinflammation; Parkinson’s disease; scRNA-Seq; α-Synuclein
    DOI:  https://doi.org/10.1186/s12974-024-03210-8
  27. bioRxiv. 2024 Aug 22. pii: 2024.08.22.609230. [Epub ahead of print]
    Variant-to-function mapping of late-onset Alzheimer's disease GWAS signals in human microglial cell models implicates RTFDC1 at the CASS4 locus.
    Elizabeth A Burton, Mariana Argenziano, Kieona Cook, Molly Ridler, Sumei Lu, Chun Su, Elisabetta Manduchi, Sheridan H Littleton, Michelle E Leonard, Kenyaita M Hodge, Li-San Wang, Gerard D Schellenberg, Matthew E Johnson, Matthew C Pahl, James A Pippin, Andrew D Wells, Stewart A Anderson, Christopher D Brown, Struan F A Grant, Alessandra Chesi.
      Late-onset Alzheimer's disease (LOAD) research has principally focused on neurons over the years due to their known role in the production of amyloid beta plaques and neurofibrillary tangles. In contrast, recent genomic studies of LOAD have implicated microglia as culprits of the prolonged inflammation exacerbating the neurodegeneration observed in patient brains. Indeed, recent LOAD genome-wide association studies (GWAS) have reported multiple loci near genes related to microglial function, including TREM2 , ABI3 , and CR1 . However, GWAS alone cannot pinpoint underlying causal variants or effector genes at such loci, as most signals reside in non-coding regions of the genome and could presumably confer their influence frequently via long-range regulatory interactions. We elected to carry out a combination of ATAC-seq and high-resolution promoter-focused Capture-C in two human microglial cell models (iPSC-derived microglia and HMC3) in order to physically map interactions between LOAD GWAS-implicated candidate causal variants and their corresponding putative effector genes. Notably, we observed consistent evidence that rs6024870 at the GWAS CASS4 locus contacted the promoter of nearby gene, RTFDC1 . We subsequently observed a directionallly consistent decrease in RTFDC1 expression with the the protective minor A allele of rs6024870 via both luciferase assays in HMC3 cells and expression studies in primary human microglia. Through CRISPR-Cas9-mediated deletion of the putative regulatory region harboring rs6024870 in HMC3 cells, we observed increased pro-inflammatory cytokine secretion and decreased DNA double strand break repair related, at least in part, to RTFDC1 expression levels. Our variant-to-function approach therefore reveals that the rs6024870-harboring regulatory element at the LOAD ' CASS4' GWAS locus influences both microglial inflammatory capacity and DNA damage resolution, along with cumulative evidence implicating RTFDC1 as a novel candidate effector gene.
    DOI:  https://doi.org/10.1101/2024.08.22.609230
  28. J Neuroinflammation. 2024 Aug 31. 21(1): 214
    Microglia LILRB4 upregulation reduces brain damage after acute ischemic stroke by limiting CD8+ T cell recruitment.
    Yilin Ma, Kai Zheng, Chengcheng Zhao, Jieli Chen, Lin Chen, Yue Zhang, Tao Chen, Xiuhua Yao, Ying Cai, Jialing Wu.
       BACKGROUND: Leukocyte immunoglobulin-like receptor B4 (LILRB4) plays a significant role in regulating immune responses. LILRB4 in microglia might influence the infiltration of peripheral T cells. However, whether and how LILRB4 expression aggravates brain damage after acute ischemic stroke remains unclear. This study investigates the role of LILRB4 in modulating the immune response and its potential protective effects against ischemic brain injury in mice.
    METHODS AND RESULTS: Microglia-specific LILRB4 conditional knockout (LILRB4-KO) and overexpression transgenic (LILRB4-TG) mice were constructed by a Cre-loxP system. Then, they were used to investigate the role of LILRB4 after ischemic stroke using a transient middle cerebral artery occlusion (tMCAO) mouse model. Spatial transcriptomics analysis revealed increased LILRB4 expression in the ischemic hemisphere. Single-cell RNA sequencing (scRNA-seq) identified microglia-cluster3, an ischemia-associated microglia subcluster with elevated LILRB4 expression in the ischemic brain. Flow cytometry and immunofluorescence staining showed increased CD8+ T cell infiltration into the brain in LILRB4-KO-tMCAO mice. Behavioral tests, cortical perfusion maps, and infarct size measurements indicated that LILRB4-KO-tMCAO mice had more severe functional deficits and larger infarct sizes compared to Control-tMCAO and LILRB4-TG-tMCAO mice. T cell migration assays demonstrated that LILRB4-KD microglia promoted CD8+ T cell recruitment and activation in vitro, which was mitigated by CCL2 inhibition and recombinant arginase-1 addition. The scRNA-seq and spatial transcriptomics identified CCL2 was predominantly secreted from activated microglia/macrophage and increased CCL2 expression in LILRB4-KD microglia, suggesting a chemokine-mediated mechanism of LILRB4.
    CONCLUSION: LILRB4 in microglia plays a crucial role in modulating the post-stroke immune response by regulating CD8+ T cell infiltration and activation. Knockout of LILRB4 exacerbates ischemic brain injury by promoting CD8+ T cell recruitment. Overexpression of LILRB4, conversely, offers neuroprotection. These findings highlight the therapeutic potential of targeting LILRB4 and its downstream pathways to mitigate immune-mediated damage in ischemic stroke.
    Keywords:  CD8+ T cells; Ischemic stroke; LILRB4; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-024-03206-4
  29. Adv Neurobiol. 2024 ;37 531-544
    Interpretation of Neurodegenerative GWAS Risk Alleles in Microglia and their Interplay with Other Cell Types.
    Inge R Holtman, Christopher K Glass, Alexi Nott.
      Microglia have been implicated in numerous neurodegenerative and neuroinflammatory disorders; however, the causal contribution of this immune cell type is frequently debated. Genetic studies offer a unique vantage point in that they infer causality over a secondary consequence. Genome-wide association studies (GWASs) have identified hundreds of loci in the genome that are associated with susceptibility to neurodegenerative disorders. GWAS studies implicate microglia in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and to a lesser degree suggest a role for microglia in vascular dementia (VaD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and other neurodegenerative and neuropsychiatric disorders. The contribution and function of GWAS risk loci on disease progression is an ongoing field of study, in which large genomic datasets, and an extensive framework of computational tools, have proven to be crucial. Several GWAS risk loci are shared between disorders, pointing towards common pleiotropic mechanisms. In this chapter, we introduce key concepts in GWAS and post-GWAS interpretation of neurodegenerative disorders, with a focus on GWAS risk genes implicated in microglia, their interplay with other cell types and shared convergence of GWAS risk loci on microglia.
    Keywords:  Dementia; GWAS; Genetic-overlap; Heterogeneity; Microglia; Neurodegeneration
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_29
  30. Adv Neurobiol. 2024 ;37 53-63
    Visualization, Fate Mapping, Ablation, and Mutagenesis of Microglia in the Mouse Brain.
    Jung-Seok Kim, Steffen Jung.
      Since the classical studies of Pío del Río-Hortega, microglia research has come a long way. In particular, recent advances in bulk and single-cell (sc) transcriptomics have yielded many fascinating new insights into these intriguing immune cells at the interface with the central nervous system (CNS), both in small animal models and human samples. In parallel, tools developed by advanced mouse genetics have revealed the unique ontogeny of microglia and their striking dynamic interactions with other cells in the brain parenchyma. In this chapter, we will discuss various applications of the Cre/loxP-based approach that have enabled the study of microglia in their physiological context of the mouse brain. We will highlight selected key findings that have shaped our current understanding of these cells and discuss the technical intricacies of the Cre/loxP approach and some remaining challenges.
    Keywords:  Fate mapping; Microglia; Ontogeny; Technologies; Transgenic mouse models
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_4
  31. Acta Neuropathol Commun. 2024 Aug 28. 12(1): 139
    Deciphering glial contributions to CSF1R-related disorder via single-nuclear transcriptomic profiling: a case study.
    Jie Pan, Jaume Fores-Martos, Claire Delpirou Nouh, Tanner D Jensen, Kristen Vallejo, Romain Cayrol, Saman Ahmadian, Euan A Ashley, Michael D Greicius, Inma Cobos.
      CSF1R-related disorder (CSF1R-RD) is a neurodegenerative condition that predominantly affects white matter due to genetic alterations in the CSF1R gene, which is expressed by microglia. We studied an elderly man with a hereditary, progressive dementing disorder of unclear etiology. Standard genetic testing for leukodystrophy and other neurodegenerative conditions was negative. Brain autopsy revealed classic features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), including confluent white matter degeneration with axonal spheroids and pigmented glial cells in the affected white matter, consistent with CSF1R-RD. Subsequent long-read sequencing identified a novel deletion in CSF1R that was not detectable with short-read exome sequencing. To gain insight into potential mechanisms underlying white matter degeneration in CSF1R-RD, we studied multiple brain regions exhibiting varying degrees of white matter pathology. We found decreased CSF1R transcript and protein across brain regions, including intact white matter. Single nuclear RNA sequencing (snRNAseq) identified two disease-associated microglial cell states: lipid-laden microglia (expressing GPNMB, ATG7, LGALS1, LGALS3) and inflammatory microglia (expressing IL2RA, ATP2C1, FCGBP, VSIR, SESN3), along with a small population of CD44+ peripheral monocyte-derived macrophages exhibiting migratory and phagocytic signatures. GPNMB+ lipid-laden microglia with ameboid morphology represented the end-stage disease microglia state. Disease-associated oligodendrocytes exhibited cell stress signatures and dysregulated apoptosis-related genes. Disease-associated oligodendrocyte precursor cells (OPCs) displayed a failure in their differentiation into mature myelin-forming oligodendrocytes, as evidenced by upregulated LRP1, PDGFRA, SOX5, NFIA, and downregulated NKX2-2, NKX6.2, SOX4, SOX8, TCF7L2, YY1, ZNF488. Overall, our findings highlight microglia-oligodendroglia crosstalk in demyelination, with CSF1R dysfunction promoting phagocytic and inflammatory microglia states, an arrest in OPC differentiation, and oligodendrocyte depletion.
    Keywords:  ALSP; CSF1R; GPNMB; HDLS; Leukodystrophy; Macrophage; Microglia; OPC; Oligodendrocyte
    DOI:  https://doi.org/10.1186/s40478-024-01853-5
  32. bioRxiv. 2024 Aug 22. pii: 2024.08.22.609112. [Epub ahead of print]
    Loss of Insulin Signaling in Microglia Impairs Cellular Uptake of Aβ and Neuroinflammatory Response Exacerbating Alzheimer-like Neuropathology.
    Wenqiang Chen, Xiangyu Liu, Vitor Rosetto Munoz, C Ronald Kahn.
      Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimers disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprograming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ; plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism, neuroinflammation and the ability of the cells to take up Aβ; such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.
    DOI:  https://doi.org/10.1101/2024.08.22.609112
  33. bioRxiv. 2024 Aug 12. pii: 2024.07.27.605403. [Epub ahead of print]
    Early life psychosocial stress increases binge-like ethanol consumption and CSF1R inhibition prevents stress-induced alterations in microglia and brain macrophage population density.
    Stephen C Gironda, Samuel W Centanni, Jeffrey L Weiner.
      Early life stress (ELS) has lasting consequences on microglia and brain macrophage function. During ELS, microglia and brain macrophages alter their engagement with synapses leading to changes in neuronal excitability. Further, ELS can induce innate immune memory formation in microglia and brain macrophages resulting in altered responsivity to future environmental stimuli. These alterations can result in lasting adaptations in circuit function and may mediate the relationship between ELS and the risk to develop alcohol use disorder (AUD). Whether microglia and brain macrophages truly mediate this relationship remains elusive. Here, we report: 1) an ELS model, psychosocial stress (PSS), increases binge-like ethanol consumption in early adulthood. 2) Repeated binge-like ethanol consumption increases microglia and brain macrophage population densities across the brain. 3) PSS may elicit innate immune memory formation in microglia and brain macrophages leading to altered population densities following repeated binge-like ethanol consumption. 4) Microglia and brain macrophage inhibition trended towards preventing PSS-evoked changes in binge-like ethanol consumption and normalized microglia and brain macrophage population densities. Therefore, our study suggests that acutely inhibiting microglia and brain macrophage function during periods of early life PSS may prevent innate immune memory formation and assist in reducing the risk to develop AUD.
    Highlights: An early life psychosocial stress (PSS) exposure increases ethanol consumptionMicroglial inhibition during PSS trends towards reducing ethanol consumptionBinge ethanol consumption increases microglial count and alters cell proximityEarly life PSS alters microglial responsivity to binge ethanol consumptionMicroglial inhibition may prevent microglial innate immune memory formation.
    DOI:  https://doi.org/10.1101/2024.07.27.605403
  34. Adv Neurobiol. 2024 ;37 65-80
    Progress in Structural and Functional In Vivo Imaging of Microglia and Their Application in Health and Disease.
    Alexis Crockett, Martin Fuhrmann, Olga Garaschuk, Dimitrios Davalos.
      The first line of defense for the central nervous system (CNS) against injury or disease is provided by microglia. Microglia were long believed to stay in a dormant/resting state, reacting only to injury or disease. This view changed dramatically with the development of modern imaging techniques that allowed the study of microglial behavior in the intact brain over time, to reveal the dynamic nature of their responses. Over the past two decades, in vivo imaging using multiphoton microscopy has revealed numerous new functions of microglia in the developing, adult, aged, injured, and diseased CNS. As the most dynamic cells in the brain, microglia continuously contact all structures and cell types, such as glial and vascular cells, neuronal cell bodies, axons, dendrites, and dendritic spines, and are believed to play a central role in sculpting neuronal networks throughout life. Following trauma, or in neurodegenerative or neuroinflammatory diseases, microglial responses range from protective to harmful, underscoring the need to better understand their diverse roles and states in different pathological conditions. In this chapter, we introduce multiphoton microscopy and discuss recent advances in structural and functional imaging technologies that have expanded our toolbox to study microglial states and behaviors in new ways and depths. We also discuss relevant mouse models available for in vivo imaging studies of microglia and review how such studies are constantly refining our understanding of the multifaceted role of microglia in the healthy and diseased CNS.
    Keywords:  Alzheimer’s disease; Imaging technologies and methods; In vitro experiments; In vivo imaging; Microglia; Mouse models; Multiple sclerosis; Two-photon microscopy
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_5
  35. bioRxiv. 2024 Aug 15. pii: 2024.08.15.608133. [Epub ahead of print]
    Microglia morphology in the developing primate amygdala and effects of early life stress.
    Dennisha P King, Miral Abdalaziz, Ania K Majewska, Judy L Cameron, Julie L Fudge.
      A unique pool of immature glutamatergic neurons in the primate amygdala, known as the paralaminar nucleus (PL), are maturing between infancy and adolescence. The PL is a potential substrate for the steep growth curve of amygdala volume during this developmental period. A microglial component is also embedded among the PL neurons, and likely supports local neuronal maturation and emerging synaptogenesis. Microglia may alter neuronal growth following environmental perturbations such as stress. Using multiple measures, we first found that microglia in the infant primate PL had relatively large somas, and a small arbor size. In contrast, microglia in the adolescent PL had a smaller soma, and a larger dendritic arbor. We then examined microglial morphology in the PL after a novel maternal separation protocol, to examine the effects of early life stress. After maternal separation, the microglia had increased soma size, arbor size and complexity. Surprisingly, strong effects were seen not only in the infant PL, but also in the adolescent PL from subjects who had experienced the separation many years earlier. We conclude that under maternal-rearing conditions, PL microglia morphology tracks PL neuronal growth, progressing to a more 'mature' phenotype by adolescence. Maternal separation has long-lasting effects on microglia, altering their normal developmental trajectory, and resulting in a 'hyper-ramified' phenotype that persists for years. We speculate that these changes have consequences for neuronal development in young primates.
    Significance Statement: The paralaminar (PL) nucleus of the amygdala is an important source of plasticity, due to its unique repository of immature glutamatergic neurons. PL immature neurons mature between birth and adolescence. This process is likely supported by synaptogenesis, which requires microglia. Between infancy and adolescence in macaques, PL microglia became more dense, and shifted to a 'ramified' phenotype, consistent with increased synaptic pruning functions. Early life stress in the form of maternal separation, however, blunted this normal trajectory, leading to persistent 'parainflammatory' microglial morphologies. We speculate that early life stress may alter PL neuronal maturation and synapse formation through microglia.
    DOI:  https://doi.org/10.1101/2024.08.15.608133
  36. Adv Neurobiol. 2024 ;37 399-403
    Microglia in Neuropathic Pain.
    Kazuhide Inoue.
      Neuropathic pain (NP) is pain resulting from lesions or disease of the somatosensory system. A cardinal feature of NP is tactile allodynia (a painful response to normally innocuous stimulation). In 2003, a breakthrough strategy for inducing NP was proposed in which microglia of the spinal dorsal horn (SDH) are activated after peripheral nerve injury (PNI) to overexpress P2X4 receptor (P2X4R) and play an important role in inducing tactile allodynia. In 2005, it was reported that stimulation of microglial P2X4Rs evokes the release of brain-derived neurotrophic factor (BDNF), which causes a depolarizing shift of the anion reversal potential (Eanion) of secondary sensory neurons. These findings and other facts suggest the mechanism by which innocuous touch stimuli cause severe pain and the important role of microglia in the mechanism.
    Keywords:  Microglia; Neuropathic pain; P2X4R; Spinal cord
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_22
  37. Adv Neurobiol. 2024 ;37 545-568
    Emerging Models to Study Human Microglia In vitro.
    Henna Jäntti, Lois Kistemaker, Alice Buonfiglioli, Lot D De Witte, Tarja Malm, Elly M Hol.
      New in vitro models provide an exciting opportunity to study live human microglia. Previously, a major limitation in understanding human microglia in health and disease has been their limited availability. Here, we provide an overview of methods to obtain human stem cell or blood monocyte-derived microglia-like cells that provide a nearly unlimited source of live human microglia for research. We address how understanding microglial ontogeny can help modeling microglial identity and function in a dish with increased accuracy. Moreover, we categorize stem cell-derived differentiation methods into embryoid body based, growth factor driven, and coculture-driven approaches, and review novel viral approaches to reprogram stem cells directly into microglia-like cells. Furthermore, we review typical readouts used in the field to verify microglial identity and characterize functional microglial phenotypes. We provide an overview of methods used to study microglia in environments more closely resembling the (developing) human CNS, such as cocultures and brain organoid systems with incorporated or innately developing microglia. We highlight how microglia-like cells can be utilized to reveal molecular and functional mechanisms in human disease context, focusing on Alzheimer's disease and other neurodegenerative diseases as well as neurodevelopmental diseases. Finally, we provide a critical overview of challenges and future opportunities to more accurately model human microglia in a dish and conclude that novel in vitro microglia-like cells provide an exciting potential to bring preclinical research of microglia to a new era.
    Keywords:  Authors Henna Jäntti and Lois Kistemaker have equally contributed to this chapter.; Brain organoid; In vitro model; Microglia; Monocyte; iPSC
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_30
  38. Adv Neurobiol. 2024 ;37 607-622
    Metabolic Control of Microglia.
    Monica Emili Garcia-Segura, Stefano Pluchino, Luca Peruzzotti-Jametti.
      Microglia, immune sentinels of the central nervous system (CNS), play a critical role in maintaining its health and integrity. This chapter delves into the concept of immunometabolism, exploring how microglial metabolism shapes their diverse immune functions. It examines the impact of cell metabolism on microglia during various CNS states, including homeostasis, development, aging, and inflammation. Particularly in CNS inflammation, the chapter discusses how metabolic rewiring in microglia can initiate, resolve, or perpetuate inflammatory responses. The potential of targeting microglial metabolism as a therapeutic strategy for chronic CNS disorders with prominent innate immune cell activation is also explored.
    Keywords:  Immunometabolism; Lipid metabolism; Metabolic reprogramming; Mitochondria
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_34
  39. Adv Neurobiol. 2024 ;37 333-342
    Stress and Microglia: A Double-edged Relationship.
    Jean-Christophe Delpech, Martin Valdearcos, Agnès Nadjar.
      Microglia are highly dynamic cells and acquire different activation states to modulate their multiple functions, which are tightly regulated by the central nervous system microenvironment in which they reside. In response to stress, that is to the appearance of non-physiological signals in their vicinity, microglia will adapt their function in order to promote a return to brain homeostasis. However, when these stress signals are chronically present, microglial response may not be adapted and lead to the establishment of a pathological state. The aim of this book chapter is to examine the substantial literature around the ability of acute and chronic stressors to affect microglial structure and function, with a special focus on psychosocial and nutritional stresses. We also discuss the molecular mechanisms known to date that explain the link between exposure to stressors and microglial activation.
    Keywords:  Bioenergetics; Cytokines; Microglia; Nutrition; Stress
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_18
  40. Adv Neurobiol. 2024 ;37 379-395
    Aging Microglia and Their Impact in the Nervous System.
    Rommy von Bernhardi, Jaime Eugenín.
      Aging is the greatest risk factor for neurodegenerative diseases. Microglia are the resident immune cells in the central nervous system (CNS), playing key roles in its normal functioning, and as mediators for age-dependent changes of the CNS, condition at which they generate a hostile environment for neurons. Transforming Growth Factor β1 (TGFβ1) is a regulatory cytokine involved in immuneregulation and neuroprotection, affecting glial cell inflammatory activation, neuronal survival, and function. TGFβ1 signaling undergoes age-dependent changes affecting the regulation of microglial cells and can contribute to the pathophysiology of neurodegenerative diseases. This chapter focuses on assessing the role of age-related changes on the regulation of microglial cells and their impact on neuroinflammation and neuronal function, for understanding age-dependent changes of the nervous system.
    Keywords:  Aging; Fractalkine; Glial cells; Microglia; Neurodegenerative diseases; Neuroinflammation; TGFβ
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_21
  41. Adv Neurobiol. 2024 ;37 135-149
    Contactomics of Microglia and Intercellular Communication.
    Csaba Cserép, Balázs Pósfai, Eszter Szabadits, Ádám Dénes.
      Microglia represent the main immunocompetent cell type in the parenchyma of the brain and the spinal cord, with roles extending way beyond their immune functions. While emerging data show the pivotal role of microglia in brain development, brain health and brain diseases, the exact mechanisms through which microglia contribute to complex neuroimmune interactions are still largely unclear. Understanding the communication between microglia and other cells represents an important cornerstone of these interactions, which may provide novel opportunities for therapeutic interventions in neurological or psychiatric disorders. As such, in line with studying the effects of the numerous soluble mediators that influence neuroimmune processes, attention on physical interactions between microglia and other cells in the CNS has increased substantially in recent years. In this chapter, we briefly summarize the latest literature on "microglial contactomics" and its functional implications in health and disease.
    Keywords:  Brain disease; Cell–cell interactions; Contactomics; Inflammation; Microglia
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_8
  42. Adv Neurobiol. 2024 ;37 579-589
    Microglial Positron Emission Tomography Imaging In Vivo : Positron Emission Tomography Radioligands: Utility in Research and Clinical Practice.
    Julie Ottoy, Livia De Picker, Min Su Kang.
      Microglia, the resident immune cells of the central nervous system (CNS) play a key role in regulating and maintaining homeostasis in the brain. However, the CNS is also vulnerable to infections and inflammatory processes. In response to CNS perturbations, microglia become reactive, notably with expression of the translocator protein (TSPO), primarily on their outer mitochondrial membrane. Despite TSPO being commonly used as a marker for microglia, it is also present in other cell types such as astrocytes. Positron emission tomography (PET) ligands that target the TSPO enable the noninvasive detection and quantification of glial reactivity. While some limitations were raised, TSPO PET remains an attractive biomarker of CNS infection and inflammation. This book chapter delves into the development and application of microglial PET imaging with a focus on the TSPO PET. First, we provide an overview of the evolution of TSPO PET radioligands from first-generation to second-generation ligands and their applications in studying neuroinflammation (or CNS inflammation). Subsequently, we discuss the limitations and challenges associated with TSPO PET. Then we go on to explore non-TSPO targets for microglial PET imaging. Finally, we conclude with future directions for research and clinical practice in this field.
    Keywords:  CNS inflammation; Glia; Microglia; Neuroinflammation; PET; TSPO
    DOI:  https://doi.org/10.1007/978-3-031-55529-9_32
  43. Proteins. 2024 Sep 01.
    Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States.
    Madison K Kuhn, Elizabeth A Proctor.
      Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer's disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets. Extensive evidence gathered using transgenic mouse models supports an active role of microglia in pathology progression, though results vary and can be contradictory between different types of models and the degree of pathology at the time of study. Here, we review microglial immune signaling and responses that contribute to the accumulation and spread of pathological proteins or directly affect neuronal health. We additionally explore the use of induced pluripotent stem cell (iPSC)-derived models to study living human microglia and how they have contributed to our knowledge of AD and may begin to fill in the gaps left by mouse models. Ultimately, mouse and iPSC-derived models have their own limitations, and a comprehensive understanding of microglial dysfunction in AD will only be established by an integrated view across models and an appreciation for their complementary viewpoints and limitations.
    Keywords:  Alzheimer's disease; amyloid‐β; microglia; protein aggregation; proteinopathy; tau protein
    DOI:  https://doi.org/10.1002/prot.26723
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