bims-microg 2024-11-17 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024–11–17
twenty-two papers selected by
Marcus Karlstetter, Universität zu Köln

Differential contributions of fetal mononuclear phagocytes to Zika virus neuroinvasion versus neuroprotection during congenital infection.
Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP/PS1/tau mice.
Human-induced pluripotent stem cell-derived microglia integrate into mouse retina and recapitulate features of endogenous microglia.
The microglial translocator protein (TSPO) in Alzheimer's disease reflects a phagocytic phenotype.
Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown.
Peripheral CD4+ T cell phenotype and brain microglial activation associated with cognitive heterogeneity in aged rats.
Up-regulated succinylation modifications induce a senescence phenotype in microglia by altering mitochondrial energy metabolism.
APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia.
Decoding physiological and pathological roles of innate immune cells in eye diseases: the perspectives from single-cell RNA sequencing.
Stress-induced obesity in mice causes cognitive decline associated with inhibition of hippocampal neurogenesis and dysfunctional gut microbiota.
Pharmacogenomic screening identifies and repurposes leucovorin and dyclonine as pro-oligodendrogenic compounds in brain repair.
Discovery of the First-in-Class Dual TSPO/Carbonic Anhydrase Modulators with Promising Neurotrophic Activity.
Non-resolving neuroinflammation regulates axon regeneration in chronic spinal cord injury.
ZBTB18 regulates cytokine expression and affects microglia/macrophage recruitment and commitment in glioblastoma.
Macrophage exosomal miR-30c-2-3p in atherosclerotic plaques aggravates microglial neuroinflammation during large-artery atherosclerotic stroke via TGF-β/SMAD2 pathway.
Psilocin, the Psychoactive Metabolite of Psilocybin, Modulates Select Neuroimmune Functions of Microglial Cells in a 5-HT2 Receptor-Dependent Manner.
Complement and microglia activation mediate stress-induced synapse loss in layer 2/3 of the medial prefrontal cortex in male mice.
NAD+ supplement relieved chronic sleep restriction (CSR)-induced microglial proinflammation in vivo and in vitro.
Prolactin deficiency drives diabetes-associated cognitive dysfunction by inducing microglia-mediated synaptic loss.
scRNA-Seq reveals age-dependent microglial evolution as a determinant of immune response following spinal cord injury.
Gene expression profiles of endothelium, microglia and oligodendrocytes in hippocampus of post-stroke depression rat at single cell resolution.
Microglia-Dependent Peripheral Neuropathic Pain in Adulthood Following Adolescent Exposure to Morphine in Male Rats.

Cell. 2024 Nov 06. pii: S0092-8674(24)01210-8. [Epub ahead of print]

Differential contributions of fetal mononuclear phagocytes to Zika virus neuroinvasion versus neuroprotection during congenital infection.

Muhammad Abdelbasset, Wilfried A A Saron, Dongliang Ma, Abhay P S Rathore, Tatsuya Kozaki, Chengwei Zhong, Chinmay Kumar Mantri, Yingrou Tan, Chi-Ching Tung, Hong Liang Tey, Justin Jang Hann Chu, Jinmiao Chen, Lai Guan Ng, Hongyan Wang, Florent Ginhoux, Ashley L St John.

  Fetal immune cell functions during congenital infections are poorly understood. Zika virus (ZIKV) can vertically transmit from mother to fetus, causing nervous system infection and congenital ZIKV syndrome (CZS). We identified differential functional roles for fetal monocyte/macrophage cell types and microglia in ZIKV dissemination versus clearance using mouse models. Trafficking of ZIKV-infected primitive macrophages from the yolk sac allowed initial fetal virus inoculation, while recruited monocytes promoted non-productive neuroinflammation. Conversely, brain-resident differentiated microglia were protective, limiting infection and neuronal death. Single-cell RNA sequencing identified transcriptional profiles linked to the protective versus detrimental contributions of mononuclear phagocyte subsets. In human brain organoids, microglia also promoted neuroprotective transcriptional changes and infection clearance. Thus, microglia are protective before birth, contrasting with the disease-enhancing roles of primitive macrophages and monocytes. Differential modulation of myeloid cell phenotypes by genetically divergent ZIKVs underscores the potential of immune cells to regulate diverse outcomes during fetal infections.

Keywords:  Zika virus; congenital Zika syndrome; fetal immunity; infection; microglia; monocytes; mononuclear phagocytes; myeloid cells; primitive macrophages; scRNA-seq

DOI:  https://doi.org/10.1016/j.cell.2024.10.028
Neuroscience. 2024 Nov 13. pii: S0306-4522(24)00604-3. [Epub ahead of print]

Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP/PS1/tau mice.

Zhao-Jun Wang, Wei-Na Han, Shi-Fan Chai, Yan Li, Chao-Jing Fu, Chen-Fang Wang, Hong-Yan Cai, Xin-Yi Li, Xiao Wang, Christian Hölscher, Mei-Na Wu.

  A growing number of studies show that the diabetes drug Semaglutide is neuroprotective in Alzheimer's disease (AD) animal models, but its mode of action is not fully understood. In order to explore the mechanism of Semaglutide, 7-month-old APP/PS1/tau transgenic (3xTg) mice and wild-type (WT) mice were randomly divided into four groups: control group (WT + PBS), AD model group (3xTg + PBS), Semaglutide control group (WT + Semaglutide) and Semaglutide treatment group (3xTg + Semaglutide). Semaglutide (25 nmol/kg) or PBS was administered intraperitoneally once every two days for 30 days, followed by behavioral and molecular experiments. The results show that Semaglutide can improve working memory and spatial reference memory of 3xTg-AD mice, promote the release of anti-inflammatory factors and inhibit the production of pro-inflammatory factors in the cortex and hippocampus, and reduce Aβ deposition in the hippocampal CA1 region of 3xTg mice. Semaglutide can inhibit the apoptosis of BV2 cells induced by Aβ1-42 in a dose-dependent manner and promote the transformation of microglia from M1 to M2, thereby exerting anti-inflammatory and neuroprotective effects. Therefore, we speculate that Semaglutide shows an anti-inflammatory effect by promoting the transformation of microglia from M1 to M2 type in the brain of 3xTg mice, and thus exerts a neuroprotective effect.

Keywords:  Alzheimer’s disease; GLP-1 receptor agonist; Microglia; Neuroinflammation; Semaglutide

DOI:  https://doi.org/10.1016/j.neuroscience.2024.11.022
Elife. 2024 Nov 08. pii: RP90695. [Epub ahead of print]12

Human-induced pluripotent stem cell-derived microglia integrate into mouse retina and recapitulate features of endogenous microglia.

Wenxin Ma, Lian Zhao, Biying Xu, Robert N Fariss, T Michael Redmond, Jizhong Zou, Wai T Wong, Wei Li.

  Microglia exhibit both maladaptive and adaptive roles in the pathogenesis of neurodegenerative diseases and have emerged as a cellular target for central nervous system (CNS) disorders, including those affecting the retina. Replacing maladaptive microglia, such as those impacted by aging or over-activation, with exogenous microglia that can enable adaptive functions has been proposed as a potential therapeutic strategy for neurodegenerative diseases. To investigate microglia replacement as an approach for retinal diseases, we first employed a protocol to efficiently generate human-induced pluripotent stem cell (hiPSC)-derived microglia in quantities sufficient for in vivo transplantation. These cells demonstrated expression of microglia-enriched genes and showed typical microglial functions such as LPS-induced responses and phagocytosis. We then performed xenotransplantation of these hiPSC-derived microglia into the subretinal space of adult mice whose endogenous retinal microglia have been pharmacologically depleted. Long-term analysis post-transplantation demonstrated that transplanted hiPSC-derived microglia successfully integrated into the neuroretina as ramified cells, occupying positions previously filled by the endogenous microglia and expressed microglia homeostatic markers such as P2ry12 and Tmem119. Furthermore, these cells were found juxtaposed alongside residual endogenous murine microglia for up to 8 months in the retina, indicating their ability to establish a stable homeostatic state in vivo. Following retinal pigment epithelial cell injury, transplanted microglia demonstrated responses typical of endogenous microglia, including migration, proliferation, and phagocytosis. Our findings indicate the feasibility of microglial transplantation and integration in the retina and suggest that modulating microglia through replacement may be a therapeutic strategy for treating neurodegenerative retinal diseases.

Keywords:  NaIO3; PLX-5622; RPE; human iPSC; microglia; mouse; regenerative medicine; retinal transplantation; stem cells

DOI:  https://doi.org/10.7554/eLife.90695
Acta Neuropathol. 2024 Nov 14. 148(1): 62

The microglial translocator protein (TSPO) in Alzheimer's disease reflects a phagocytic phenotype.

Emma F Garland, Henrike Antony, Laura Kulagowska, Thomas Scott, Charlotte Rogien, Michel Bottlaender, James A R Nicoll, Delphine Boche.

  Translocator protein (TSPO) is a mitochondrial protein expressed by microglia, ligands for which are used as a marker of neuroinflammation in PET studies of Alzheimer's disease (AD). We previously showed increasing TSPO load in the cerebral cortex with AD progression, consistent with TSPO PET scan findings. Here, we aim to characterise the microglial phenotype associated with TSPO expression to aid interpretation of the signal generated by TSPO ligands in patients. Human post-mortem sections of temporal lobe (TL) and cerebellum (Cb) from cases classified by Braak group (0-II, III-IV, V-VI; each n = 10) were fluorescently double labelled for TSPO and microglial markers: Iba1, HLA-DR, CD68, MSR-A and CD64. Quantification was performed on scanned images using QuPath software to assess the microglial phenotype of TSPO. Qualitative analysis was also performed for TSPO with GFAP (astrocytes), CD31 (endothelial cells) and CD163 (perivascular macrophages) to characterise the cellular profile of TSPO. The percentage of CD68+TSPO+ double-labelled cells was significantly higher than for other microglial markers in both brain regions and in all Braak stages, followed by MSR-A+TSPO+ microglia. Iba1+TSPO+ cells were more numerous in the cerebellum than the temporal lobe, while CD64+TSPO+ cells were more numerous in the temporal lobe. No differences were observed for the other microglial markers. TSPO expression was also detected in endothelial cells, but not detected in astrocytes nor in perivascular macrophages. Our data suggest that TSPO is mainly related to a phagocytic profile of microglia (CD68+) in human AD, potentially highlighting the ongoing neurodegeneration.

Keywords:  Alzheimer’s disease; Human; Inflammation; Microglia; Translocator protein

DOI:  https://doi.org/10.1007/s00401-024-02822-x
JCI Insight. 2024 Nov 08. pii: e180081. [Epub ahead of print]9(21):

Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown.

Jennifer H Lawrence, Asha Patel, Melvin W King, Collin J Nadarajah, Richard Daneman, Erik S Musiek.

  The blood-brain barrier (BBB) is critical for maintaining brain homeostasis but is susceptible to inflammatory dysfunction. While transporter-dependent efflux of some lipophilic substrates across the BBB shows circadian variation due to rhythmic transporter expression, basal transporter-independent permeability and leakage is nonrhythmic. Whether daily timing influences BBB permeability in response to inflammation is unknown. Here, we induced systemic inflammation through repeated LPS injections either in the morning (ZT1) or evening (ZT13) under standard lighting conditions; we then examined BBB permeability to a polar molecule that is not a transporter substrate, sodium fluorescein. We observed clear diurnal variation in inflammatory BBB permeability, with a striking increase in paracellular leak across the BBB specifically following evening LPS injection. Evening LPS led to persisting glia activation as well as inflammation in the brain that was not observed in the periphery. The exaggerated evening neuroinflammation and BBB disruption were suppressed by microglial depletion or through keeping mice in constant darkness. Our data show that diurnal rhythms in microglial inflammatory responses to LPS drive daily variability in BBB breakdown and reveal time of day as a key regulator of inflammatory BBB disruption.

Keywords:  Inflammation; Innate immunity; Neurodegeneration; Neurological disorders; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.180081
Immun Ageing. 2024 Nov 14. 21(1): 81

Peripheral CD4+ T cell phenotype and brain microglial activation associated with cognitive heterogeneity in aged rats.

Lian Yu, Miao-Miao Liu, Mei-Qi Guan, Rui Wang, Xiao-Rong Yang, Xiu-Min Zhang, Jing-Jing Wei, Shu-Fen Wu, Hong Gu, Qiang Fu, Jun-Hong Guo, Yan-Li Li.

  Cognitive decline is a critical hallmark of brain aging. Although aging is a natural process, there is significant heterogeneity in cognition levels among individuals; however, the underlying mechanisms remain uncertain. In our study, we classified aged male Sprague‒Dawley rats into aged cognition-unimpaired (AU) group and aged cognition-impaired (AI) group by using an attentional set-shifting task. The transcriptome sequencing results of medial prefrontal cortex (mPFC) demonstrated significant differences in microglial activation and inflammatory response pathways between the two groups. Specifically, compared to AU rats, AI rats exhibited a greater presence of CD86-positive microglia and major histocompatibility complex class II (MHC-II)-positive microglia, along with elevated inflammatory molecules, in mPFC. Conversely, AI rats exhibited a reduction in the percentage of microglia expressing CD200R and the anti-inflammatory molecules Arg-1 and TGF-β. Additionally, peripheral blood analysis of AI rats demonstrated elevated levels of Th17 and Th1 cells, along with proinflammatory molecules; however, decreased levels of Treg cells, along with anti-inflammatory molecules, were observed in AI rats. Our research suggested that peripheral Th17/Treg cells and central microglial activation were associated with cognitive heterogeneity in aged rats. These findings may provide a new target for healthy aging.

Keywords:  Aging-associated cognitive decline; Cognitive heterogeneity; Inflammation; Microglial activation; Th17/Treg cells

DOI:  https://doi.org/10.1186/s12979-024-00486-5
J Neuroinflammation. 2024 Nov 14. 21(1): 296

Up-regulated succinylation modifications induce a senescence phenotype in microglia by altering mitochondrial energy metabolism.

Xinnan Zhao, Xiaohan Yang, Cong Du, Huimin Hao, Shuang Liu, Gang Liu, Guangyin Zhang, Kai Fan, Jianmei Ma.

  The aging of the central nervous system(CNS) is a primary contributor to neurodegenerative diseases in older individuals and significantly impacts their quality of life. Neuroinflammation, characterized by activation of microglia(MG) and release of cytokines, is closely associated with the onset of these neurodegenerative diseases. The activated status of MG is modulated by specifically programmed metabolic changes under various conditions. Succinylation, a novel post-translational modification(PTM) mainly involved in regulating mitochondrial energy metabolism pathways, remains unknown in its role in MG activation and aging. In the present study, we found that succinylation levels were significantly increased both during aging and upon lipopolysaccharide-induced(LPS-induced) MG activation undergoing metabolic reprogramming. Up-regulated succinylation induced by sirtuin 5 knockdown(Sirt5 KD) in microglial cell line BV2 resulted in significant up-regulation of aging-related genes, accompanied by impaired mitochondrial adaptability and a shift towards glycolysis as a major metabolic pathway. Furthermore, after LPS treatment, Sirt5 KD BV2 cells exhibited increased generation of reactive oxygen species(ROS), accumulation of lipid droplets, and elevated levels of lipid peroxidation. By employing immunoprecipitation, introducing point mutation to critical succinylation sites, and conducting enzyme activity assays for succinate dehydrogenase(SDH) and trifunctional enzyme subunit alpha(ECHA), we demonstrated that succinylation plays a regulatory role in modulating the activities of these mitochondrial enzymes. Finally, down-regulation the succinylation levels achieved through administration of succinyl phosphonate(SP) led to amelioration of MG senescence in vitro and neuroinflammation in vivo. To our knowledge, our data provide preliminary evidence indicating that up-regulated succinylation modifications elicit a senescence phenotype in MG through alterations in energy metabolism. Moreover, these findings suggest that manipulation of succinylation levels may offer valuable insights into the treatment of aging-related neuroinflammation.

Keywords:  Aging; Metabolic reprogramming; Microglia; Neuroinflammation; Succinylation

DOI:  https://doi.org/10.1186/s12974-024-03284-4
EMBO Mol Med. 2024 Nov 11.

APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia.

Pranav Preman, Daan Moechars, Emre Fertan, Leen Wolfs, Lutgarde Serneels, Disha Shah, Jochen Lamote, Suresh Poovathingal, An Snellinx, Renzo Mancuso, Sriram Balusu, David Klenerman, Amaia M Arranz, Mark Fiers, Bart De Strooper.

  The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.

Keywords:  APOE; Alzheimer’s Disease; Astrocytes; Microglia; β-amyloid Pathology

DOI:  https://doi.org/10.1038/s44321-024-00162-7
Front Immunol. 2024 ;15 1490719

Decoding physiological and pathological roles of innate immune cells in eye diseases: the perspectives from single-cell RNA sequencing.

Chen Lu, Xiying Mao, Songtao Yuan.

  Single-cell RNA sequencing (scRNA-seq) has facilitated a deeper comprehension of the molecular mechanisms behind eye diseases and has prompted the selection of precise therapeutic targets by examining the cellular and molecular intricacies at the single-cell level. This review delineates the pivotal role of scRNA-seq in elucidating the functions of innate immune cells within the context of ocular pathologies. Recent advancements in scRNA-seq have revealed that innate immune cells, both from the periphery and resident in the retina, are actively engaged in various stages of multiple eye diseases. Notably, resident microglia and infiltrating neutrophils exhibit swift responses during the initial phase of injury, while peripheral monocyte-derived macrophages exhibit transcriptomic profiles akin to those of activated microglia, suggesting their potential for long-term residence within the retina. The scRNA-seq analyses have underscored the cellular heterogeneity and gene expression alterations within innate immune cells, which, while sharing commonalities, exhibit disease-specific variations. These insights have not only broadened our understanding of the cellular and molecular mechanisms in eye diseases but also paved the way for the identification of candidate targets for targeted therapeutic interventions. The application of scRNA-seq technology has heralded a new era in the study of ocular pathologies, enabling a more detailed appreciation of the roles that innate immune cells play across a spectrum of eye diseases.

Keywords:  eye diseases; innate immunity; microglia; monocyte; neutrophil; retina; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fimmu.2024.1490719
Front Microbiol. 2024 ;15 1381423

Stress-induced obesity in mice causes cognitive decline associated with inhibition of hippocampal neurogenesis and dysfunctional gut microbiota.

Yu-E Liu, Zhihuang Zhao, Haili He, Liangyuan Li, Chenghong Xiao, Tao Zhou, Zili You, Jinqiang Zhang.

  Effects of stress on obesity have been thoroughly studied in high-fat diet fed mice, but not in normal diet fed mice, which is important to clarify because even on a normal diet, some individuals will become obese under stress conditions. Here we compared mice that showed substantial weight gain or loss under chronic mild stress while on a normal diet; we compared the two groups in terms of cognitive function, hypothalamic-pituitary-adrenal signaling, neurogenesis and activation of microglia in hippocampus, gene expression and composition of the gut microbiome. Chronic mild stress induced diet-independent obesity in approximately 20% of animals, and it involved inflammatory responses in peripheral and central nervous system as well as hyperactivation of the hypothalamic-pituitary-adrenal signaling and of microglia in the hippocampus, which were associated with cognitive deficits and impaired hippocampal neurogenesis. It significantly increased in relative abundance at the phylum level (Firmicutes), at the family level (Prevotellaceae ucg - 001 and Lachnospiraceae NK4a136), at the genus level (Dubosiella and Turicibacter) for some enteric flora, while reducing the relative abundance at the family level (Lactobacillaceae and Erysipelotrichaceae), at the genus level (Bacteroidota, Alistipes, Alloprevotella, Bifidobacterium and Desulfovibrio) for some enteric flora. These results suggest that stress, independently of diet, can induce obesity and cognitive decline that involve dysfunctional gut microbiota. These insights imply that mitigation of hypothalamic-pituitary-adrenal signaling and microglial activation as well as remodeling of gut microbiota may reverse stress-induced obesity and associated cognitive decline.

Keywords:  adult hippocampus neurogenesis; cognitive function; depression; gut microbiome; microglia; obesity; stress

DOI:  https://doi.org/10.3389/fmicb.2024.1381423
Nat Commun. 2024 Nov 13. 15(1): 9837

Pharmacogenomic screening identifies and repurposes leucovorin and dyclonine as pro-oligodendrogenic compounds in brain repair.

Jean-Baptiste Huré, Louis Foucault, Litsa Maria Ghayad, Corentine Marie, Nicolas Vachoud, Lucas Baudouin, Rihab Azmani, Natalija Ivjanin, Alvaro Arevalo-Nuevo, Morgane Pigache, Lamia Bouslama-Oueghlani, Julie-Anne Chemelle, Marie-Aimée Dronne, Raphaël Terreux, Bassem Hassan, François Gueyffier, Olivier Raineteau, Carlos Parras.

Oligodendrocytes are critical for CNS myelin formation and are involved in preterm-birth brain injury (PBI) and multiple sclerosis (MS), both of which lack effective treatments. We present a pharmacogenomic approach that identifies compounds with potent pro-oligodendrogenic activity, selected through a scoring strategy (OligoScore) based on their modulation of oligodendrogenic and (re)myelination-related transcriptional programs. Through in vitro neural and oligodendrocyte progenitor cell (OPC) cultures, ex vivo cerebellar explants, and in vivo mouse models of PBI and MS, we identify FDA-approved leucovorin and dyclonine as promising candidates. In a neonatal chronic hypoxia mouse model mimicking PBI, both compounds promote neural progenitor cell proliferation and oligodendroglial fate acquisition, with leucovorin further enhancing differentiation. In an adult MS model of focal de/remyelination, they improve lesion repair by promoting OPC differentiation while preserving the OPC pool. Additionally, they shift microglia from a pro-inflammatory to a pro-regenerative profile and enhance myelin debris clearance. These findings support the repurposing of leucovorin and dyclonine for clinical trials targeting myelin disorders, offering potential therapeutic avenues for PBI and MS.

DOI: https://doi.org/10.1038/s41467-024-54003-9
ACS Chem Neurosci. 2024 Nov 15.

Discovery of the First-in-Class Dual TSPO/Carbonic Anhydrase Modulators with Promising Neurotrophic Activity.

Valeria Poggetti, Elisa Angeloni, Lorenzo Germelli, Benito Natale, Muhammad Waqas, Giuliana Sarno, Andrea Angeli, Simona Daniele, Silvia Salerno, Elisabetta Barresi, Sandro Cosconati, Sabrina Castellano, Eleonora Da Pozzo, Barbara Costa, Claudiu T Supuran, Federico Da Settimo, Sabrina Taliani.

  In searching for putative new therapeutic strategies to treat neurodegenerative diseases, the mitochondrial 18 kDa translocator protein (TSPO) and cerebral isoforms of carbonic anhydrase (CA) were exploited as potential targets. Based on the structures of a class of highly affine and selective TSPO ligands and a class of CA activators, both developed by us in recent years, a small library of 2-phenylindole-based dual TSPO/CA modulators was developed, able to bind TSPO and activate CA VII in the low micromolar/submicromolar range. The interaction with the two targets was corroborated by computational studies. Biological investigation on human microglia C20 cells identified derivative 3 as a promising lead compound worthy of future optimization due to its (i) lack of cytotoxicity, (ii) ability to stimulate TSPO steroidogenic function and activate CA VII, and (iii) ability to effectively upregulate gene expression of the brain-derived neurotrophic factor.

Keywords:  2-phenylindole; carbonic anhydrases; multitarget-directed ligands; neurodegenerative diseases; neuroprotection; translocator protein

DOI:  https://doi.org/10.1021/acschemneuro.4c00477
J Neurosci. 2024 Nov 07. pii: e1017242024. [Epub ahead of print]

Non-resolving neuroinflammation regulates axon regeneration in chronic spinal cord injury.

Andrew N Stewart, Christopher C Bosse-Joseph, Reena Kumari, William M Bailey, Kennedy A Park, Victoria K Slone, John C Gensel.

Chronic spinal cord injury (SCI) lesions retain increased densities of microglia and macrophages. In acute SCI, macrophages induce growth cone collapse and facilitate axon retraction away from lesion boundaries. Little is known about the role of sustained inflammation in chronic SCI, or whether chronic inflammation affects regeneration. We used the CSF1R inhibitor, PLX-5622, to deplete microglia and macrophages months after complete crush SCI in female mice. Transcriptional analyses revealed a significant inflammatory depletion within chronic SCI lesions after PLX-5622 treatment. Both transcriptional analyses and immunohistochemistry revealed that Iba1+ cells repopulate to pre-depleted densities after treatment removal. Neuronal-enriched transcripts were significantly elevated in mice after inflammatory repopulation, but no significant effects were observed with inflammatory depletion alone. Axon densities also significantly increased within the lesion after PLX-5622 treatment and after repopulation. To better examine the effect of chronic inflammation on axon regeneration, we tested PLX-5622 treatment in neuronal-specific PTEN knockout (PTEN-KO) mice. PTEN-KO was delivered using spinal injections of retrogradely transported adeno-associated viruses (AAVrg's). PTEN-KO did not further increase axon densities within the lesion beyond effects induced by PLX-5622. Axons that grew within the lesion were histologically identified as 5-HT+ and CGRP+, both of which are not robustly transduced by AAVrg's. Our work identified that increased macrophage/microglia densities in the chronic SCI environment may be actively retained by homeostatic mechanisms likely affiliated with a sustained elevated expression of CSF1 and other chemokines. Finally, we identify a novel role of sustained inflammation as a prospective barrier to axon regeneration in chronic SCI.Significance Statement Inflammatory macrophages infiltrate the spinal cord after a spinal cord injury (SCI) and remain at elevated densities around the lesion chronically. Little is known about the consequences of sustained spinal inflammation in chronic SCI, but it is known that macrophages impair regeneration early after SCI. We hypothesized that persistent neuroinflammation may function as a sustained barrier that chronically impairs axon regeneration. Our work identifies that the chronic SCI environment actively maintains increased densities of macrophages and implicates sustained inflammation as a persistent barrier to repair. Findings from our work change our understanding of the maintenance of non-resolving inflammation in chronic SCI and identifies a need to focus on overcoming chronic inflammatory barriers that limit repair after neurotrauma.

DOI: https://doi.org/10.1523/JNEUROSCI.1017-24.2024
Commun Biol. 2024 Nov 08. 7(1): 1472

ZBTB18 regulates cytokine expression and affects microglia/macrophage recruitment and commitment in glioblastoma.

Roberto Ferrarese, Kevin Joseph, Geoffroy Andrieux, Ira Verena Haase, Francesca Zanon, Eva Kling, Annalisa Izzo, Eyleen Corrales, Marius Schwabenland, Marco Prinz, Vidhya Madapusi Ravi, Melanie Boerries, Dieter Henrik Heiland, Maria Stella Carro.

Glioma associated macrophages/microglia (GAMs) play an important role in glioblastoma (GBM) progression, due to their massive recruitment to the tumor site and polarization to a tumor promoting phenotype. GAMs secrete a variety of cytokines, which facilitate tumor cell growth and invasion, and prevent other immune cells from mounting an immune response against the tumor. Here, we demonstrate that zinc finger and BTB containing domain 18 (ZBTB18), a transcriptional repressor with tumor suppressive function in glioblastoma, impairs the production of key cytokines, which function as chemoattractant for GAMs. Consistently, we observe a reduced migration of GAMs when ZBTB18 is expressed by glioblastoma cells, both in cell culture and in vivo experiments. Moreover, RNA sequencing analysis shows that the presence of ZBTB18 in glioblastoma cells alters the commitment of conditioned microglia, suggesting the loss of the immune-suppressive phenotype and the acquisition of pro-inflammatory features. Thus, therapeutic approaches to increase ZBTB18 expression in GBM cells could represent an effective adjuvant to immune therapy in GBM.

DOI: https://doi.org/10.1038/s42003-024-07144-y
J Neuroinflammation. 2024 Nov 08. 21(1): 292

Macrophage exosomal miR-30c-2-3p in atherosclerotic plaques aggravates microglial neuroinflammation during large-artery atherosclerotic stroke via TGF-β/SMAD2 pathway.

Yue Tang, Ming-Hao Dong, Xiao-Wei Pang, Hang Zhang, Yun-Hui Chu, Luo-Qi Zhou, Sheng Yang, Lu-Yang Zhang, Yun-Fan You, Li-Fang Zhu, Wei Wang, Chuan Qin, Dai-Shi Tian.

  Circulating miR-30c-2-3p has been closely related to vascular diseases, however, its role and underlying mechanisms in ischemic stroke remained unclear. Our study addressed this gap by observing elevated levels of exosomal miR-30c-2-3p in patients with acute ischemic stroke due to large artery atherosclerosis. Further investigation revealed that these exosomal miR-30c-2-3p primarily originated from macrophages within atherosclerotic plaques, exacerbating ischemic stroke by targeting microglia. Exosomes enriched with miR-30c-2-3p increased microglial inflammatory properties in vivo and aggravated neuroinflammation by inhibiting SMAD2. In summary, our findings revealed a novel mechanism whereby macrophage-derived foam cells within atherosclerotic plaques secrete exosomes with high levels of miR-30c-2-3p, thus aggravate brain damage during ischemic stroke, which serves as crucial link between the periphery and brain.

Keywords:  Atherosclerosis; Exosomes; Inflammation; MiR-30c-2-3p; Microglia

DOI:  https://doi.org/10.1186/s12974-024-03281-7
Molecules. 2024 Oct 28. pii: 5084. [Epub ahead of print]29(21):

Psilocin, the Psychoactive Metabolite of Psilocybin, Modulates Select Neuroimmune Functions of Microglial Cells in a 5-HT2 Receptor-Dependent Manner.

Kennedy R Wiens, Noah A H Brooks, Ishvin Riar, Bridget K Greuel, Ivan A Lindhout, Andis Klegeris.

  Neuroinflammation that is caused by microglia, the main immune cells of the brain, contributes to neurodegenerative diseases. Psychedelics, including psilocybin and lysergic acid diethylamide (LSD), possess certain anti-inflammatory properties and, therefore, should be considered as drug candidates for treating neuroinflammatory pathologies. When ingested, psilocybin is rapidly dephosphorylated to yield psilocin, which crosses the blood-brain barrier and exerts psychotropic activity by interacting with the 5-hydroxytryptamine 2A receptors (5-HT2ARs) on neurons. Since microglia express all three 5-HT2R isoforms, we hypothesized that, by interacting with these receptors, psilocin beneficially modulates select neuroimmune functions of microglia. We used microglia-like cell lines to demonstrate that psilocin, at non-toxic concentrations, did not affect the secretion of tumor necrosis factor (TNF) by immune-stimulated microglial cells, but significantly inhibited their phagocytic activity, the release of reactive oxygen species (ROS), and nitric oxide (NO) production. The inhibitory activity of psilocin on the latter two functions was similar to that of two selective 5-HT2R agonists, namely, 25I-NBOH and Ro60-0175. The role of this subfamily of receptors was further demonstrated by the application of 5-HT2R antagonists cyproheptadine and risperidone. Psilocin should be considered a novel drug candidate that might be effective in treating neuroimmune disorders, such as neurodegenerative diseases, where reactive microglia are significant contributors.

Keywords:  5-hydroxytryptamine; affective disorders; depression; neurodegenerative diseases; neuroprotection; phagocytic activity; reactive nitrogen species; reactive oxygen species; serotonin

DOI:  https://doi.org/10.3390/molecules29215084
Nat Commun. 2024 Nov 12. 15(1): 9803

Complement and microglia activation mediate stress-induced synapse loss in layer 2/3 of the medial prefrontal cortex in male mice.

Haven Tillmon, Breeanne M Soteros, Liang Shen, Qifei Cong, Mackenna Wollet, Julianne General, Hanna Chin, John Beichen Lee, Flavia R Carreno, David A Morilak, Jun Hee Kim, Gek Ming Sia.

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the medial prefrontal cortex (mPFC) in male mice. Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (Apoehigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the Apoehigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases.

DOI: https://doi.org/10.1038/s41467-024-54007-5
J Neuroimmunol. 2024 Oct 24. pii: S0165-5728(24)00188-7. [Epub ahead of print]397 578469

NAD+ supplement relieved chronic sleep restriction (CSR)-induced microglial proinflammation in vivo and in vitro.

Qiqiang Chen, Jinrong Xiao, Zhenya Lin, Xin Xu, Jinlan Chen.

  Sleep insufficiency is a significant health problem worldwide and can induce multiple neurodevelopmental disorders in the central nervous system (CNS). Sleep deprivation (SD), especially chronic SD, leads to cognition and memory loss and worsens neurodegenerative disease liability. Microglia are the main inflammation-dominant glia and play a crucial role in SD-induced neurological impairments. Nicotinamide adenine dinucleotide (NAD+) is a redox reaction coenzyme that exerts anti-inflammatory and mitochondria-protective effects in microglia. Whether NAD+ mitigated SD-induced neurological disorders by regulating microglial functions is still unknown. In the current study, we designed an in vivo and in vitro model to evaluate the neuroprotective effect of NAD+ on chronic sleep restriction (CSR) and further investigate the underlying mechanisms. Behavioral tests and immunofluorescence staining were applied to investigate the cognition impairments and microglial activation. Biochemical experiments were tested to analyze the oxidative status and possible mechanism. In vitro data were used to verify the in vivo data. Our results displayed that NAD+ supplement mitigated CSR-induced cognitive decline and microglial activation response by suppressing the expression of pro-inflammatory cytokines in vivo. NAD+ administration also decreased oxidative stress and mitochondrial impairments in microglia. In vitro results showed that NAD+ treatment inhibited ROS production and prompted M1 conversion to M2 phenotype. cGAS-STING/NF-κB pathways were significantly activated but down-regulated by NAD+ administration. H151, a STING antagonist, was applied to validate that NAD+ treatment alleviates neuroinflammation partially by regulating cGAS-STING pathways in microglia. Our findings suggest that NAD+ supplement is a promising therapy for sleep disorders-induced neurological problems, and cGAS-STING pathway may act as a critical regulator in microglial proinflammation.

Keywords:  Cognitive impairment; Microglia; NAD; NF-κB; STING; Sleep deprivation

DOI:  https://doi.org/10.1016/j.jneuroim.2024.578469
J Neuroinflammation. 2024 Nov 14. 21(1): 295

Prolactin deficiency drives diabetes-associated cognitive dysfunction by inducing microglia-mediated synaptic loss.

Jiaxuan Jiang, Pengzi Zhang, Yue Yuan, Xiang Xu, Tianyu Wu, Zhou Zhang, Jin Wang, Yan Bi.

   BACKGROUND: Diabetes-associated cognitive dysfunction, characterized by hippocampal synaptic loss as an early pathological feature, seriously threatens patients' quality of life. Synapses are dynamic structures, and hormones play important roles in modulating the formation and elimination of synapses. The pituitary, the master gland of the body, releases several hormones with multiple roles in hippocampal synaptic regulation. In this study, we aimed to explore the relationship between pituitary hormones and cognitive decline in diabetes.
METHODS: A total of 744 patients with type 2 diabetes (T2DM) (445 men and 299 postmenopausal women) who underwent serum pituitary hormone level assessments, comprehensive cognitive evaluations and MRI scans were enrolled. Dynamic diet interventions were applied in both chow diet-fed mice and high-fat diet (HFD)-fed diabetic mice. The cognitive performance and hippocampal pathology of prolactin (PRL)-knockout mice, neuronal prolactin receptor (PRLR)-specific knockout mice and microglial PRLR-specific knockout mice were assessed. Microglial PRLR-specific knockout mice were fed an HFD to model diabetes. Diabetic mice received an intracerebroventricular infusion of recombinant PRL protein or vehicle.
RESULTS: This clinical study revealed that decreased PRL levels were associated with cognitive impairment and hippocampal damage in T2DM patients. In diabetic mice, PRL levels diminished before hippocampal synaptic loss and cognitive decline occurred. PRL loss could directly cause cognitive dysfunction and decreased hippocampal synaptic density. Knockout of PRLR in microglia, rather than neurons, induced hippocampal synaptic loss and cognitive impairment. Furthermore, blockade of PRL/PRLR signaling in microglia exacerbated abnormal microglial phagocytosis of synapses, further aggravating hippocampal synaptic loss and cognitive impairment in diabetic mice. Moreover, PRL infusion reduced microglia-mediated synaptic loss, thereby alleviating cognitive impairment in diabetic mice.
CONCLUSION: PRL is associated with cognitive dysfunction and hippocampal damage in T2DM patients. In diabetes, a decrease in PRL level drives hippocampal synaptic loss and cognitive impairment by increasing microglia-mediated synapse engulfment. Restoration of PRL levels ameliorates cognitive dysfunction and hippocampal synaptic loss in diabetic mice.

Keywords:  Cognitive dysfunction; Diabetes mellitus; Microglia; Phagocytosis; Prolactin; Synapses

DOI:  https://doi.org/10.1186/s12974-024-03289-z
Brain Res Bull. 2024 Nov 06. pii: S0361-9230(24)00250-8. [Epub ahead of print]219 111116

scRNA-Seq reveals age-dependent microglial evolution as a determinant of immune response following spinal cord injury.

Lufei Shao, Yueliang Chang, Jinfang Liu, Leilei Lin, Long Chang, Jialin Zhang, Zhibin Lan, Honglai Zhang, Xiaolei Chen.

  Spinal cord injury (SCI) is a debilitating condition of the central nervous system (CNS) that leads to severe impairments in sensory and motor functions. Previous studies have pointed out that patient age is a critical factor influencing SCI prognosis. However, the role of microglia in age-related differences in SCI outcomes remains unclear. The current study aims to identify specific microglial subtypes and investigate their responses and functional differences in SCI recovery across different age groups. Single-cell RNA sequencing (scRNA-seq) data were obtained from the Gene Expression Omnibus (GEO) database, integrating multiple datasets to identify microglial subtypes. We performed pseudotime trajectory analysis and cell-cell communication analysis to understand microglial differentiation and interactions. Finally, immunofluorescence staining of mouse model samples was conducted to validate our bioinformatics findings. Microglia were classified into four subtypes: Homeostatic, Proliferating, Inflammatory A, and Inflammatory B. The Young SCI group exhibited a higher proportion of Homeostatic microglia and Inflammatory microglia A, whereas the old SCI group had more Inflammatory Microglia B but lacked Homeostatic Microglia. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that markers for homeostasis microglia were enriched in immune modulation pathways. While makers for Inflammatory Microglia were enriched in immune response pathways. Specifically, markers for Inflammatory microglia B were enriched in pathways associated with overactive immune response. Pseudotime analysis indicated that microglia in young mice predominantly differentiated into Inflammatory Microglia A and Homeostatic Microglia, whereas in old mice, they tended to only differentiate into Inflammatory Microglia B. CellChat analysis showed increased pro-inflammatory signaling generated by Inflammatory Microglia B, exclusively in the old group. Our study demonstrates significant differences in microglial subtypes and functions between different age groups following SCI. These findings provide novel insights into the development of age-related therapeutic strategies and microglia-targeted biological treatments for SCI.

Keywords:  Age-dependent differences; Immune response; Microglial evolution; Single-cell RNA sequencing; Spinal cord injury

DOI:  https://doi.org/10.1016/j.brainresbull.2024.111116
Mol Psychiatry. 2024 Nov 09.

Gene expression profiles of endothelium, microglia and oligodendrocytes in hippocampus of post-stroke depression rat at single cell resolution.

Cai Li, Wentao Li, Wenbin Wei, Qili Chen, Han Gao, Yanqing Zhao, Lingling Zhang, Li Ling, Hao Shen, Yifen Shen, Yihang Shen.

Post-stroke depression (PSD) is a common but severe mental complication after stroke. However, the cellular and molecular understanding of PSD is still yet to be illustrated. In current study, we prepared PSD rat model (MD) via unilateral middle cerebral artery occlusion (MCAO) and chronic stress stimulation (DEPR), and isolated hippocampal tissues for single cell sequencing of 10x Genomics Chromium. First, we determined the presence of the increased cell population of endothelium and microglia and the compromised oligodendrocytes in MD compared to NC, MCAO and DEPR. The enriched functions of highly variable genes (HVGs) of endothelium and microglia suggested a reinforced blood-brain barrier in MD. Next, cell clusters of endothelium, microglia and oligodendrocytes were individually analyzed, and the subtypes with distinct functions were identified. The presence of expression profiles, intercellular communications and signaling pathways of these three cell populations of PSD displayed a similar but more aggressive appearance with DEPR compared to MCAO and NC. Taken together, this study characterized the specific gene profile of endothelium, microglia and oligodendrocytes of hippocampal PSD by single cell sequencing, emphasizing the crosstalk among them to provide theoretical basis for the in-depth mechanism research and drug therapy of PSD.

DOI: https://doi.org/10.1038/s41380-024-02810-3
Neuropharmacology. 2024 Nov 07. pii: S0028-3908(24)00380-0. [Epub ahead of print] 110211

Microglia-Dependent Peripheral Neuropathic Pain in Adulthood Following Adolescent Exposure to Morphine in Male Rats.

Kawsar Alami, Yaghoub Fathollahi, Shiva Hashemizadeh, Masoumeh Mosleh, Saeed Semnanian, Sayed Yousof Mousavi, Hossein Azizi.

  Persistent effects of adolescent morphine exposure on neurobiological processes and behaviors in adulthood have been partially identified. Hypersensitivity following adolescent exposure to morphine is a complex and multifaceted phenomenon whose underlying mechanisms remain largely unknown. This study aimed to investigate the involvement of microglia in neuropathic pain sensitivity following adolescent morphine exposure, focused on hippocampal genes expression and plasticity. To achieve this, adolescent male Wistar rats received morphine, along with minocycline, to inhibit microglial activity. The allodynia and hyperalgesia of adult rats were evaluated using von-Frey filaments and the Hargreaves plantar test in both baseline and neuropathic pain conditions. Hippocampal genes expression was analyzed following the behavioral tests. The plasticity of the Schaffer-CA1 hippocampal synapses was also assessed using field potential recording following neuropathy. Results showed that adolescent morphine exposure exacerbated the allodynia and hyperalgesia in both baseline and neuropathic pain states in adult rats, which was significantly reduced by the co-administration of minocycline during adolescence. Neuropathy in adult rats was found to increase hippocampal expression of inflammatory mediators, but adolescent morphine prevented this effect. Additionally, we observed a reduction in the baseline synaptic transmission and long-term potentiation (LTP) at the Schaffer-CA1 hippocampal synapses after neuropathy in adult rats following adolescent exposure to morphine. The reduction of synaptic activity was not altered by the co-administration of minocycline with morphine during adolescence. It is concluded that microglia play an important role in mediating hypersensitivity induced by adolescent morphine exposure, although hippocampal microglia may not be directly involved in this process.

Keywords:  Adolescence; Hyperalgesia; Neuropathy; Opioid; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.neuropharm.2024.110211