bims-microg Biomed News
on Microglia in health and disease
Issue of 2025–02–02
35 papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice.
  2. Ibuprofen reduces inflammation, necroptosis and protects photoreceptors from light-induced retinal degeneration.
  3. REDD1-dependent GSK3β signaling in podocytes promotes canonical NF-κB activation in diabetic nephropathy.
  4. P2X7R antagonism suppresses long-lasting brain hyperexcitability following traumatic brain injury in mice.
  5. Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation.
  6. C3/C3aR Bridges Spinal Astrocyte-Microglia Crosstalk and Accelerates Neuroinflammation in Morphine-Tolerant Rats.
  7. Characteristics of TSPO expression in marmoset EAE.
  8. The ABC transporter A7 modulates neuroinflammation via NLRP3 inflammasome in Alzheimer's disease mice.
  9. Alzheimer's disease risk ABCA7 p.A696S variant disturbs the microglial response to amyloid pathology in mice.
  10. Inflammatory microglia correlate with impaired oligodendrocyte maturation in multiple sclerosis.
  11. S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss.
  12. Agmatine suppresses glycolysis via the PI3K/Akt/mTOR/HIF-1α signaling pathway and improves mitochondrial function in microglia exposed to lipopolysaccharide.
  13. Development and characterization of in vitro inducible immortalization of a murine microglia cell line for high throughput studies.
  14. ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation.
  15. Gene expression of psychiatric disorder-related kinesin superfamily proteins (Kifs) is potentiated in alternatively activated primary cultured microglia.
  16. Senescent microglia: The hidden culprits accelerating Alzheimer's disease.
  17. The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer's disease.
  18. Extracellular Vesicles From Bone Marrow-Derived Macrophages Enriched in ARG1 Enhance Microglial Phagocytosis and Haematoma Clearance Following Intracerebral Haemorrhage.
  19. Nobiletin and Eriodictyol Suppress Release of IL-1β, CXCL8, IL-6, and MMP-9 from LPS, SARS-CoV-2 Spike Protein, and Ochratoxin A-Stimulated Human Microglia.
  20. Diabetes Mellitus Impairs Blood-Brain Barrier Integrality and Microglial Reactivity.
  21. Long non-coding RNA Malat1 modulates CXCR4 expression to regulate the interaction between induced neural stem cells and microglia following closed head injury.
  22. Microglia-Derived Interleukin-6 Triggers Astrocyte Apoptosis in the Hippocampus and Mediates Depression-Like Behavior.
  23. Inhibition of CD36 ameliorates mouse spinal cord injury by accelerating microglial lipophagy.
  24. Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy.
  25. A microglial kinase ITK mediating neuroinflammation and behavioral deficits in traumatic brain injury.
  26. Prenatal inflammation impairs early CD11c-positive microglia induction and delays myelination in neurodevelopmental disorders.
  27. 7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in Alzheimer's disease.
  28. Hyperhomocysteinemia-induced VCID results in visual deficits, reduced neuroinflammation and vascular alterations in the retina.
  29. α-Synuclein fibrils enhance HIV-1 infection of human T cells, macrophages and microglia.
  30. Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation.
  31. The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity.
  32. Circulating miR-574-5p shows diagnostic and prognostic significance and regulates oxygen-glucose deprivation (OGD)-induced inflammatory activation of microglia by targeting ATP2B2.
  33. IL-18 Blockage Reduces Neuroinflammation and Promotes Functional Recovery in a Mouse Model of Spinal Cord Injury.
  34. Single-Cell RNA-Seq Uncovers Robust Glial Cell Transcriptional Changes in Methamphetamine-Administered Mice.
  35. Serum starvation induces cytosolic DNA trafficking via exosome and autophagy-lysosome pathway in microglia.
  1. Nat Commun. 2025 Jan 15. 16(1): 699
    Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice.
    Sung-Hyun Yoon, Chae Youn Kim, Eunju Lee, Changjun Lee, Kyung-Seo Lee, Jaeho Lee, Hana Park, Bokeum Choi, Inhwa Hwang, Junhan Kim, Tae-Gyun Kim, Junghyun Son, Young-Min Hyun, Seunghee Hong, Je-Wook Yu.
      Blood-brain barrier (BBB) disintegration is a key contributor to neuroinflammation; however, the biological processes governing BBB permeability under physiological conditions remain unclear. Here, we investigate the role of NLRP3 inflammasome in BBB disruption following peripheral inflammatory challenges. Repeated intraperitoneal lipopolysaccharide administration causes NLRP3-dependent BBB permeabilization and myeloid cell infiltration into the brain. Using a mouse model with cell-specific hyperactivation of NLRP3, we identify microglial NLRP3 activation as essential for peripheral inflammation-induced BBB disruption. Conversely, NLRP3 and microglial gasdermin D (GSDMD) deficiency markedly attenuates lipopolysaccharide-induced BBB breakdown. Notably, IL-1β is not required for NLRP3-GSDMD-mediated BBB disruption. Instead, microglial NLRP3-GSDMD axis upregulates CXCL chemokines and matrix metalloproteinases around BBB via producing GDF-15, promoting the recruitment of CXCR2-containing neutrophils. Inhibition of neutrophil infiltration and matrix metalloproteinase activity significantly reduces NLRP3-mediated BBB impairment. Collectively, these findings reveal the important role of NLRP3-driven chemokine production in BBB disintegration, suggesting potential therapeutic targets to mitigate neuroinflammation.
    DOI:  https://doi.org/10.1038/s41467-025-56097-1
  2. J Neuroinflammation. 2025 Jan 28. 22(1): 20
    Ibuprofen reduces inflammation, necroptosis and protects photoreceptors from light-induced retinal degeneration.
    Ping-Wu Zhang, Zi-He Wan, Weifeng Li, Abhishek Vats, Kunal Mehta, Laura Fan, Lingli Zhou, Sean Li, Gloria Li, Casey J Keuthan, Cynthia Berlinicke, Cheng Qian, Noriko Esumi, Elia J Duh, Donald J Zack.
       BACKGROUND: The retinal degenerative diseases retinitis pigmentosa (RP) and atrophic age- related macular degeneration (AMD) are characterized by vision loss from photoreceptor (PR) degeneration. Unfortunately, current treatments for these diseases are limited at best. Genetic and other preclinical evidence suggest a relationship between retinal degeneration and inflammation. To further explore this relationship, we tested whether Ibuprofen (IBU), an FDA-approved non-steroidal anti-inflammatory drug (NSAID), could promote PR survival and function in a mouse model of light damage (LD)-induced PR degeneration.
    METHODS: LD was induced by exposing mice to 4000 lx of light for 2-4 hours (h). IBU (100 or 200 mg/kg) or vehicle was administered by daily intraperitoneal injection. Retinal structure and function were evaluated by spectral-domain optical coherence tomography (SD-OCT) and electroretinography (ERG). Cell death genes were analyzed at 24 and 72 h after LD using the Mouse Pan-Cell Death Pathway PCR Array (88 genes). The cellular location and protein expression of key necroptosis genes were assessed by immunohistochemistry.
    RESULTS: Retinal outer nuclear layer (ONL) thickness in vehicle-injected LD animals was 8.7 ± 0.6% of retinas without LD (p < 0.0001). In IBU 200 mg/kg treated mice, central ONL thickness was 74.9 ± 7.7% of untreated retinas (p < 0.001). A-wave and b-wave ERG amplitudes were significantly preserved in IBU-treated animals. IBU significantly inhibited retinal inflammation. Twenty-four hour after LD, retinal mRNA expression for the inflammatory-factors tumor necrosis factor (Tnf), interleukin-1 beta (Il1B), and C-C motif chemokine ligand 2 (Ccl2) increased by 10-, 17-, and 533-fold, respectively; in IBU-treated animals, the expression levels of these inflammatory factors were not significantly different from no-LD controls. Expression of key necroptosis genes, including Ripk3 and Mlkl, were upregulated in LD vehicle-treated mice, but dramatically reduced to near no LD levels in LD IBU-treated mice. Microglia activation and MLKL protein upregulation were observed primarily in photoreceptors 12 h after LD, as assessed by immunohistochemistry. IBU reduced the upregulation of MLKL protein and microglia migration in the ONL and outer plexiform layer (OPL) of treated retinas.
    CONCLUSIONS: Systemic administration of the anti-inflammatory drug IBU partially protected mouse retinas from light-induced photochemical damage and inhibited both inflammation and the necroptosis cell death pathways. Our results suggest that NSAIDs may provide a promising therapeutic approach for treatment of the human retinal degenerative diseases.
    Keywords:  Ibuprofen; Inflammation; Macular degeneration; Necroptosis; Neuroprotection; Photoreceptor; Retina; Retinal degeneration; Retinitis pigmentosa
    DOI:  https://doi.org/10.1186/s12974-024-03329-8
  3. J Biol Chem. 2025 Jan 27. pii: S0021-9258(25)00091-2. [Epub ahead of print] 108244
    REDD1-dependent GSK3β signaling in podocytes promotes canonical NF-κB activation in diabetic nephropathy.
    Siddharth Sunilkumar, Esma I Yerlikaya, Ashley VanCleave, Sandeep M Subrahmanian, Allyson L Toro, Scot R Kimball, Michael D Dennis.
      Increasing evidence supports the role of an augmented immune response in the early development and progression of renal complications caused by diabetes. We recently demonstrated that podocyte-specific expression of stress response protein regulated in development and DNA damage response 1 (REDD1) contributes to activation of the pro-inflammatory transcription factor NF-κB in the kidney of diabetic mice. The studies here were designed to define the specific signaling events whereby REDD1 promotes NF-κB activation in the context of diabetic nephropathy. Streptozotocin (STZ)-induced diabetes promoted activation of glycogen synthase kinase 3β (GSK3β) in the kidney, which was prevented by REDD1 ablation. REDD1 was necessary and sufficient to enhance GSK3β activity in human podocyte cultures exposed to hyperglycemic conditions. GSK3β suppression prevented NF-κB activation and normalized the expression of pro-inflammatory factors in podocytes exposed to hyperglycemic conditions. In the kidneys of diabetic mice and in podocytes exposed to hyperglycemic conditions, REDD1-dependent GSK3β signaling promoted activation of the inhibitor of κB (IκB) kinase (IKK) complex upstream of NF-κB. GSK3β knockdown in podocytes exposed to hyperglycemic conditions reduced macrophage chemotaxis. Similarly, in diabetic mice treated with a GSK3 inhibitor, immune cell infiltration in the kidneys was reduced. Overall, the data support a model wherein hyperglycemia amplifies the activation of GSK3β in a REDD1-dependent manner, leading to canonical NF-κB signaling and an augmented renal immune response in diabetic nephropathy.
    Keywords:  DDIT4; diabetic nephropathy; glycogen synthase kinase 3 (GSK‐3); inflammation; podocyte
    DOI:  https://doi.org/10.1016/j.jbc.2025.108244
  4. Theranostics. 2025 ;15(4): 1399-1419
    P2X7R antagonism suppresses long-lasting brain hyperexcitability following traumatic brain injury in mice.
    Mariana Alves, Laura de Diego-Garcia, Gloria Vegliante, Oscar Moreno, Beatriz Gil, Pedro Ramos-Cabrer, Meghma Mitra, Ana Fernandez Martin, Aida Menéndez-Méndez, Yitao Wang, Nathan Ryzewski Strogulski, Meng-Juan Sun, Ciara Melia, Giorgia Conte, Sandra Plaza-García, Igor Khalin, Xinchen Teng, Nikolaus Plesnila, Bert Klebl, Klaus Dinkel, Michael Hamacher, Anindya Bhattacharya, Marc Ceusters, James Palmer, David J Loane, Jordi Llop, David C Henshall, Tobias Engel.
      Purpose: Post-traumatic epilepsy (PTE) is one of the most common life-quality reducing consequences of traumatic brain injury (TBI). However, to date there are no pharmacological approaches to predict or to prevent the development of PTE. The P2X7 receptor (P2X7R) is a cationic ATP-dependent membrane channel that is expressed throughout the brain. While increasing evidence suggests a role for the P2X7R during seizures and epilepsy, it is unclear if changes in P2X7R expression can predict TBI-induced epilepsy development, and whether P2X7R antagonism can protect against long-lasting brain hyperexcitability caused by TBI. Methods: TBI was induced in adult male mice using the controlled cortical impact model (CCI). To test the anti-epileptogenic effects of P2X7R antagonism, mice were treated with brain-penetrant P2X7R antagonists JNJ-54175446 (30 mg/kg) or AFC-5128 (30 mg/kg) for 7 days post-CCI. The cell-type specific effects of P2X7Rs on TBI-induced hyperexcitability were analyzed in mice lacking exon 2 of the P2rx7 gene selectively in microglia (P2rx7:Cx3cr1-Cre). Static positron emission tomography (PET) via an intravenous injection of the P2X7R radioligand 18F-JNJ-64413739 and magnetic resonance imaging (MRI) were conducted twice during the first- and third-week post-injury. Results: Following TBI, while there were no obvious changes in P2X7R protein levels in the ipsilateral hippocampus post-injury, there was a delayed increase in P2X7R protein levels in the ipsilateral cortex at 3 months post-injury. Treatment with P2X7R antagonists shortly after TBI reduced long-lasting brain hyperexcitability, reduced cortical contusion volume, and normalized injury-induced hyperactivity to control sham-levels at 3 weeks post-TBI. Notably, mice lacking P2rx7 in microglia had an increased seizure threshold after TBI, suggesting that P2X7R contributed to brain hyperexcitability via its effects on microglia. Finally, P2X7R radioligand uptake after TBI correlated with seizure threshold at 3 weeks post-injury. Conclusions: Our results demonstrate the antiepileptogenic potential of P2X7R antagonism to prevent TBI-induced epilepsy and indicate that P2X7R-based PET imaging may be a useful diagnostic tool to identify people at risk of developing PTE.
    Keywords:  Epileptogenesis; Magnetic Resonance Imaging; Microglia; P2X7 Receptor; Positron Emission Tomography; Post-traumatic Epilepsy; Traumatic Brain Injury
    DOI:  https://doi.org/10.7150/thno.97254
  5. PLoS Genet. 2025 Jan;21(1): e1011525
    Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation.
    Dylan Carter-Cusack, Stephen Huang, Sahar Keshvari, Omkar Patkar, Anuj Sehgal, Rachel Allavena, Robert A J Byrne, B Paul Morgan, Stephen J Bush, Kim M Summers, Katharine M Irvine, David A Hume.
      Adaptation to existence outside the womb is a key event in the life of a mammal. The absence of macrophages in rats with a homozygous mutation in the colony-stimulating factor 1 receptor (Csf1r) gene (Csf1rko) severely compromises pre-weaning somatic growth and maturation of organ function. Transfer of wild-type bone marrow cells (BMT) at weaning rescues tissue macrophage populations permitting normal development and long-term survival. To dissect the phenotype and function of macrophages in postnatal development, we generated transcriptomic profiles of all major organs of wild-type and Csf1rko rats at weaning and in selected organs following rescue by BMT. The transcriptomic profiles revealed subtle effects of macrophage deficiency on development of all major organs. Network analysis revealed a common signature of CSF1R-dependent resident tissue macrophages that includes the components of complement C1Q (C1qa/b/c genes). Circulating C1Q was almost undetectable in Csf1rko rats and rapidly restored to normal levels following BMT. Tissue-specific macrophage signatures were also identified, notably including sinus macrophage populations in the lymph nodes. Their loss in Csf1rko rats was confirmed by immunohistochemical localisation of CD209B (SIGNR1). By 6-12 weeks, Csf1rko rats succumb to emphysema-like pathology associated with the selective loss of interstitial macrophages and granulocytosis. This pathology was reversed by BMT. Along with physiological rescue, BMT precisely regenerated the abundance and expression profiles of resident macrophages. The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia. In addition, the transferred BM failed to restore blood monocyte or CSF1R-positive bone marrow progenitors. These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity.
    DOI:  https://doi.org/10.1371/journal.pgen.1011525
  6. CNS Neurosci Ther. 2025 Jan;31(1): e70216
    C3/C3aR Bridges Spinal Astrocyte-Microglia Crosstalk and Accelerates Neuroinflammation in Morphine-Tolerant Rats.
    Xiaoling Peng, Jie Ju, Zheng Li, Jie Liu, Xiaoqian Jia, Jihong Wang, Jihao Ren, Feng Gao.
       AIMS: Communication within glial cells acts as a pivotal intermediary factor in modulating neuroimmune pathology. Meanwhile, an increasing awareness has emerged regarding the detrimental role of glial cells and neuroinflammation in morphine tolerance (MT). This study investigated the influence of crosstalk between astrocyte and microglia on the evolution of morphine tolerance.
    METHODS: Sprague-Dawley rats were intrathecally treated with morphine twice daily for 9 days to establish morphine-tolerant rat model. Tail-flick latency test was performed to identify the analgesic effect of morphine. The role of microglia, astrocyte and C3-C3aR axis in morphine tolerance were elucidated by real-time quantitative polymerase chain reaction, Western blot, and immunofluorescence.
    RESULTS: Chronic morphine treatment notably promoted the activation of microglia, upregulated the production of proinflammatory mediators (interleukin-1 alpha (IL-1α), tumor necrosis factor alpha (TNFα), and complement component 1q (C1q)). Simultaneously, it programed astrocytes to a pro-inflammatory phenotype (A1), which mainly expresses complement 3 (C3) and serping1. PLX3397 (a colony-stimulating factor 1 receptor (CSF1R) inhibitor), Compstain (a C3 inhibitor) and SB290157(a C3aR antagonist) could reverse the above pathological process and alleviate morphine tolerance to different extents.
    CONCLUSION: Our findings identify C3-C3aR axis as an amplifier of microglia-astrocyte crosstalk, neuroinflammation and a node for therapeutic intervention in morphine tolerance.
    Keywords:  A1 astrocyte; C3/C3aR; microglia‐astrocyte crosstalk; morphine tolerance
    DOI:  https://doi.org/10.1111/cns.70216
  7. J Neuroinflammation. 2025 Jan 27. 22(1): 19
    Characteristics of TSPO expression in marmoset EAE.
    Irene Falk, Dragan Maric, Emily Leibovitch, Pascal Sati, Jennifer Lefeuvre, Nicholas J Luciano, Joseph Guy, Seung-Kwon Ha, David R Owen, Franklin Aigbirhio, Paul M Matthews, Daniel S Reich, Steven Jacobson.
      Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and is a leading non-traumatic cause of disability in young adults. The 18 kDa Translocator Protein (TSPO) is a mitochondrial protein and positron emission tomography (PET)-imaging target that is highly expressed in MS brain lesions. It is used as an inflammatory biomarker and has been proposed as a therapeutic target. However, its specific pathological significance in humans is not well understood. Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a well-established primate model of MS. Studying TSPO expression in this model will enhance our understanding of its expression in MS. This study therefore characterizes patterns of TSPO expression in fixed CNS tissues from one non-EAE control marmoset and 8 EAE marmosets using multiplex immunofluorescence. In control CNS tissue, we find that TSPO is expressed in the leptomeninges, ependyma, and over two-thirds of Iba1 + microglia, but not astrocytes or neurons. In Iba1 + cells in both control and acute EAE tissue, we find that TSPO is co-expressed with markers of antigen presentation (CD74), early activation (MRP14), phagocytosis (CD163) and anti-inflammatory phenotype (Arg1); a high level of TSPO expression is not restricted to a particular microglial phenotype. While TSPO is expressed in over 88% of activated Iba1 + cells in acute lesions in marmoset EAE, it also is sometimes observed in subsets of astrocytes and neurons. Additionally, we find the percentage of Iba1 + cells expressing TSPO declines significantly in lesions > 5 months old and may be as low as 13% in chronic lesions. However, we also find increased astrocytic TSPO expression in chronic-appearing lesions with astrogliosis. Finally, we find expression of TSPO in a subset of neurons, most frequently GLS2 + glutamatergic neurons. The shift in TSPO expression from Iba + microglia/macrophages to astrocytes over time is similar to patterns suggested by earlier neuropathology studies in MS. Thus, marmoset EAE appears to be a clinically relevant model for the study of TSPO in immune dysregulation in human disease.
    Keywords:  Experimental autoimmune encephalomyelitis; Multiple sclerosis; PET imaging; TSPO
    DOI:  https://doi.org/10.1186/s12974-025-03343-4
  8. Alzheimers Res Ther. 2025 Jan 27. 17(1): 30
    The ABC transporter A7 modulates neuroinflammation via NLRP3 inflammasome in Alzheimer's disease mice.
    Irene Santos-García, Pablo Bascuñana, Mirjam Brackhan, María Villa, Ivan Eiriz, Thomas Brüning, Jens Pahnke.
       BACKGROUND: Specific genetic variants in the ATP-binding cassette transporter A7 locus (ABCA7) are associated with an increased risk of Alzheimer's disease (AD). ABCA7 transports lipids from/across cell membranes, regulates Aβ peptide processing and clearance, and modulates microglial and T-cell functions to maintain immune homeostasis in the brain. During AD pathogenesis, neuroinflammation is one of the key mechanisms involved. Therefore, we wanted to investigate the specific role of ABCA7 in microglial activation via the NLRP3 inflammasome.
    METHODS: We developed the first humanized, Cre-inducible ABCA7flx knock-in mouse model, crossbred it with the APPPS1-21 β-amyloidosis model, and generated constitutive ABCA7ko and microglia Cx3cr1-specific conditional ABCA7ko AD mice. The role of ABCA7 was analyzed using histological, biochemical, molecular and mass spectrometry methods.
    RESULTS: Constitutive knockout of the Abca7 gene in APPPS1 mice increased the levels of Aβ42 and the number of IBA1+ (microglia) and GFAP+ (astrocytes) cells. Changes in the levels of astrocytes and microglia are associated with the activation of the NLRP3 inflammasome and increased levels of proinflammatory cytokines, such as IL1β and TNFα. Interestingly, microglia-specific ABCA7ko restored Aβ42 peptide levels and IBA1+ and GFAP+ and NLRP3-related gene expression to the original APPPS1 mouse levels. In primary glial cell cultures of APPPS1-hA7ko microglia and APPPS1 astrocytes from newborn pups, we observed that conditioned media from LPS-stimulated microglia was able to induce NLRP3 inflammasome expression and proinflammatory cytokine release in astrocytes.
    CONCLUSIONS: Our data suggest that ABCA7 transporters regulate the communication between microglia and astrocytes through the NLRP3 inflammasome and the release of proinflammatory cytokines. This regulation implicates ABCA7 as a key driver ultimately involved in the persistence of the inflammatory response observed in AD.
    Keywords:  ABC transporter; ABCA7; APPPS1-21; Alzheimer’s disease; Astrocytes; Cx3cr1; Inflammasome; Microglia; NLRP3
    DOI:  https://doi.org/10.1186/s13195-025-01673-2
  9. Neurobiol Dis. 2025 Jan 27. pii: S0969-9961(25)00029-4. [Epub ahead of print]206 106813
    Alzheimer's disease risk ABCA7 p.A696S variant disturbs the microglial response to amyloid pathology in mice.
    Xiaoye Ma, Dmitry Prokopenko, Ni Wang, Tomonori Aikawa, Younjung Choi, Can Zhang, Dan Lei, Yingxue Ren, Keiji Kawatani, Skylar C Starling, Ralph B Perkerson, Bhaskar Roy, Astrid C Quintero, Tammee M Parsons, Yining Pan, Zonghua Li, Minghui Wang, Hanmei Bao, Xianlin Han, Guojun Bu, Rudolph E Tanzi, Takahisa Kanekiyo.
      The adenosine triphosphate-binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer's disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque-associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34-positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7. ONE SENTENCE SUMMARY: A rare Alzheimer's disease risk ABCA7 p.A696S variant compromises microglial response to amyloid pathology.
    Keywords:  ABCA7; Alzheimer's disease; Amyloid-β; Lipids; Microglia
    DOI:  https://doi.org/10.1016/j.nbd.2025.106813
  10. Front Immunol. 2024 ;15 1522381
    Inflammatory microglia correlate with impaired oligodendrocyte maturation in multiple sclerosis.
    J Q Alida Chen, Dennis D Wever, Niamh B McNamara, Morjana Bourik, Joost Smolders, Jörg Hamann, Inge Huitinga.
       Introduction: Remyelination of demyelinated axons can occur as an endogenous repair mechanism in multiple sclerosis (MS), but its efficacy varies between both MS individuals and lesions. The molecular and cellular mechanisms that drive remyelination remain poorly understood. Here, we studied the relation between microglia activation and remyelination activity in MS.
    Methods: We correlated regenerative (CD163+) and inflammatory (iNOS+) microglia with BCAS1+ oligodendrocytes, subdivided into early-stage (<3 processes) and late-stage (≥3 processes) cells in brain donors with high or low remyelinating potential in remyelinated lesions and active lesions with ramified/amoeboid (non-foamy) or foamy microglia. A cohort of MS donors categorized as efficiently remyelinating donors (ERDs; n=25) or poorly remyelinating donors (PRDs; n=17) was included, based on their proportion of remyelinated lesions at autopsy.
    Results and discussion: We hypothesized more CD163+ microglia and BCAS1+ oligodendrocytes in remyelinated and active non-foamy lesions from ERDs and more iNOS+ microglia with fewer BCAS1+ oligodendrocytes in active foamy lesions from PRDs. For CD163+ microglia, however, no differences were observed between MS lesions and MS donor groups. In line with our hypothesis, we found that INOS+ microglia were significantly increased in PRDs compared to ERDs within remyelinated lesions. MS lesions, more late-stage BCAS1+ oligodendrocytes were detected in active lesions with non-foamy or foamy microglia in comparison with remyelinated lesions. Although no differences were found for early-stage BCAS1+ oligodendrocytes between MS lesions, we did find significantly more early-stage BCAS1+ oligodendrocytes in PRDs vs ERDs in remyelinated lesions. Interestingly, a positive correlation was identified between iNOS+ microglia and the presence of early-stage BCAS1+ oligodendrocytes. These findings suggest that impaired maturation of early-stage BCAS1+ oligodendrocytes, encountering inflammatory microglia, may underlie remyelination deficits and unsuccessful lesion repair in MS.
    Keywords:  inflammation; microglia; multiple sclerosis; oligodendrocytes; remyelination
    DOI:  https://doi.org/10.3389/fimmu.2024.1522381
  11. Neurobiol Dis. 2025 Jan 28. pii: S0969-9961(25)00033-6. [Epub ahead of print] 106817
    S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss.
    Katryna Pampuscenko, Silvija Jankeviciute, Ramune Morkuniene, Darius Sulskis, Vytautas Smirnovas, Guy C Brown, Vilmante Borutaite.
      S100 calcium-binding protein A9 (S100A9, also known as calgranulin B) is expressed and secreted by myeloid cells under inflammatory conditions, and S100A9 can amplify inflammation. There is a large increase in S100A9 expression in the brains of patients with neurodegenerative diseases, such as Alzheimer's disease, and S100A9 has been suggested to contribute to neurodegeneration, but the mechanisms are unclear. Here we investigated the effects of extracellular recombinant S100A9 protein on microglia, neurons and synapses in primary rat brain neuronal-glial cell cultures. Incubation of cell cultures with 250-500 nM S100A9 caused neuronal loss without signs of apoptosis or necrosis, but accompanied by exposure of the "eat-me" signal - phosphatidylserine on neurons. S100A9 caused activation of microglial inflammation as evidenced by an increase in the microglial number, morphological changes, release of pro-inflammatory cytokines, and increased phagocytic activity. At lower concentrations, 10-100 nM S100A9 induced synaptic loss in the cultures. Depletion of microglia from the cultures prevented S100A9-induced neuronal and synaptic loss, indicating that neuronal and synaptic loss was mediated by microglia. These results suggest that extracellular S100A9 may contribute to neurodegeneration by activating microglial inflammation and phagocytosis, resulting in loss of synapses and neurons. This further suggests the possibility that neurodegeneration may be reduced by targeting S100A9 or microglia.
    Keywords:  Cell death; Microglia; Neurodegeneration; Neuroinflammation; Neurotoxicity; S100A9 protein
    DOI:  https://doi.org/10.1016/j.nbd.2025.106817
  12. Biofactors. 2025 Jan-Feb;51(1):51(1): e2149
    Agmatine suppresses glycolysis via the PI3K/Akt/mTOR/HIF-1α signaling pathway and improves mitochondrial function in microglia exposed to lipopolysaccharide.
    Katarina Milosevic, Ana Milosevic, Ivana Stevanovic, Anica Zivkovic, Danijela Laketa, Marija M Janjic, Ivana Bjelobaba, Irena Lavrnja, Danijela Savic.
      Modulating metabolic pathways in activated microglia can alter their phenotype, which is relevant in uncontrolled neuroinflammation as a component of various neurodegenerative diseases. Here, we investigated how pretreatment with agmatine, an endogenous polyamine, affects metabolic changes in an in vitro model of neuroinflammation, a murine microglial BV-2 cell line exposed to lipopolysaccharide (LPS). Hence, we analyzed gene expression using qPCR and protein levels using Western blot and ELISA. Microglial metabolic status was assessed by measuring lactate release and cellular ATP by enzymatic and luminescence spectrophotometry. Mitochondrial functionality was analyzed by fluorescent probes detecting mitochondrial membrane potential (mtMP) and superoxide production. Our findings suggest that kinase pathways associated with hypoxia-inducible factor-1α (HIF-1α) regulate energy metabolism in pro-inflammatory activated microglia. We have shown that LPS induces HIF-1α and genes for glucose transporter and glycolytic rate, increases lactate production and causes mitochondrial dysfunction, suggesting a metabolic shift towards glycolysis. Agmatine inhibits the PI3K/Akt pathway and negatively regulates mammalian target of rapamycin (mTOR) phosphorylation and HIF-1α levels, reducing lactate and tumor necrosis factor (TNF) production, which is supported by pharmacological blockade of PI3K. Pretreatment with agmatine also rescues mitochondrial function by counteracting the LPS-induced decline in mtMP and increase in mitochondrial superoxide, resulting in an anti-apoptotic effect. Agmatine alone increases intracellular ATP levels and maintains this effect even under pro-inflammatory conditions. Our study emphasizes the ability of agmatine to engage in metabolic reprogramming of pro-inflammatory microglia through increased ATP production and modulation of signaling pathway involved in promoting glycolysis and cytokine release.
    Keywords:  ATP; HIF‐1α; PI3K/Akt/mTOR; agmatine; glycolysis; microglia
    DOI:  https://doi.org/10.1002/biof.2149
  13. Sci Rep. 2025 Jan 25. 15(1): 3207
    Development and characterization of in vitro inducible immortalization of a murine microglia cell line for high throughput studies.
    Hana Yeh, Matthew A De Cruz, Yang You, Seiko Ikezu, Tsuneya Ikezu.
      There are few in vitro models available to study microglial physiology in a homeostatic context. Recent approaches include the human induced pluripotent stem cell model, but these can be challenging for large-scale assays and may lead to batch variability. To advance our understanding of microglial biology while enabling scalability for high-throughput assays, we developed an inducible immortalized murine microglial cell line using a tetracycline expression system. The addition of doxycycline facilitates rapid cell proliferation, allowing for population expansion. Upon withdrawal of doxycycline, this monoclonal microglial cell line differentiates, resembling in vivo microglial physiology as demonstrated by the expression of microglial genes, innate immune responses, chemotaxis, and phagocytic abilities. We utilized live imaging and various molecular techniques to functionally characterize the clonal 2E11murine microglial cell line. Transcriptomic analysis showed that the 2E11 line exhibited characteristics of immature, proliferative microglia during doxycycline induction, and further differentiation led to a more homeostatic phenotype. Treatment with transforming growth factor-β modified the transcriptome of the 2E11 cell line, affecting cellular immune pathways. Our findings indicate that the 2E11 inducible immortalized cell line is a practical and convenient tool for studying microglial biology in vitro.
    Keywords:  Chemotaxis; Cytokines; Inducible immortalized cell line; Murine microglia; Phagocytosis; Transcriptomics
    DOI:  https://doi.org/10.1038/s41598-025-87543-1
  14. Acta Neuropathol Commun. 2025 Jan 27. 13(1): 16
    ROS-regulated SUR1-TRPM4 drives persistent activation of NLRP3 inflammasome in microglia after whole-brain radiation.
    Yuan Chang, Yihua He, Di Wang, Kunxue Zhang, Yuzhen Zhang, Zhentong Li, Shuxin Zeng, Sheng Xiao, Suyue Pan, Kaibin Huang.
      Delayed radiation-induced brain injury (RIBI) characterized by progressive cognitive decline significantly impacts patient outcomes after radiotherapy. The activation of NLRP3 inflammasome within microglia after brain radiation is involved in the progression of RIBI by mediating inflammatory responses. We have previously shown that sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) mediates microglial NLRP3-related inflammation following global brain ischemia. However, the role of SUR1-TRPM4 in RIBI remains unclear. Here, we found that whole-brain radiation induced up-regulation and assembly of SUR1-TRPM4, which further activated the NLRP3 inflammasome in microglia and caused persistent neuroinflammation in mice. Blocking SUR1-TRPM4 by glibenclamide or gene deletion of Trpm4 effectively prevented NLRP3-mediated neuroinflammation and alleviated RIBI. Utilizing the mouse model of RIBI and irradiated BV2 cells, we further demonstrated that irradiation caused mitochondrial damage to microglia, leading to violent release of reactive oxygen species (ROS), which enhanced the transcription of SUR1, TRPM4, and NLRP3 inflammasome-related molecules. Moreover, ROS up-regulated ten-eleven translocation 2 (TET2) to enhance TRPM4 expression by mediating the demethylation of the gene promoter, thereby facilitating the assembly of SUR1-TRPM4 in microglia. In summary, this study deciphers that SUR1-TRPM4 crucially mediates the persistent activation of microglial NLRP3 inflammasome under the action of ROS after whole-brain radiation, offering novel therapeutic strategies for delayed RIBI as well as other NLRP3-related neurological disorders involving excessive ROS production.
    Keywords:  Microglia; NLRP3 inflammasome; ROS; Radiation-induced brain injury; SUR1-TRPM4; TET2
    DOI:  https://doi.org/10.1186/s40478-025-01932-1
  15. BMC Res Notes. 2025 Jan 30. 18(1): 44
    Gene expression of psychiatric disorder-related kinesin superfamily proteins (Kifs) is potentiated in alternatively activated primary cultured microglia.
    Suguru Iwata, Mitsuhiro Hyugaji, Yohei Soga, Momo Morikawa, Tetsuya Sasaki, Yosuke Takei.
       OBJECTIVE: Reactivity of microglia, the resident cells of the brain, underlies innate immune mechanisms (e.g., injury repair), and disruption of microglial reactivity has been shown to facilitate psychiatric disorder dysfunctions. Although cellular analyses based on cultured microglia have been conducted, the molecular mechanism regulating microglial polarization remains elusive. We established a primary microglia culture that enabled manipulation of the substate of cells. This allowed us to investigate the expression levels of psychiatric disorder-related Kifs messenger RNA (mRNA) in each condition. Kifs encode molecular motor proteins that transport cargo along microtubules, which are thought to dynamically reorganize during a substate change.
    RESULTS: As a candidate for a crucial Kifs gene that is associated with microglia polarization, we selected psychiatric disorder-related Kifs including Kif17. We found that the relative amounts of Kif3a, Kif17, and Kif13a mRNA were potentiated in alternatively activated microglia, whereas there were no significant changes in activated microglia. Furthermore, the microglia derived from a mouse line which possesses a mutation inducing truncated KIF17 indicated disrupted morphological phenotype of alternatively activated microglia. These results suggest that the potentiation of specific molecular motor expression is required to maintain the function of alternatively activated microglia.
    Keywords:  Alternatively activated microglia; Interleukin-4; Kinesin superfamily proteins (KIFs); Microglia; Primary culture; Psychiatric disorder; Real-time qPCR
    DOI:  https://doi.org/10.1186/s13104-024-07078-y
  16. Brain Res. 2025 Jan 28. pii: S0006-8993(25)00038-1. [Epub ahead of print] 149480
    Senescent microglia: The hidden culprits accelerating Alzheimer's disease.
    Wu Li, Xie Yong-Yan, Mu Jia-Xin, Ge Shu-Chao, Huang Li-Ping.
      Ageing is a major risk factor for neurodegenerative diseases like Alzheimer's disease (AD). Microglia, as the principal innate immune cells within the brain, exert homeostatic and active immunological defense functions throughout human lifespan. The age-related dysfunction of microglia is currently recognized as a pivotal trigger for brain diseases associated with aging. In AD, microglia exhibit alterations in gene expression, cellular morphology, and functional behavior. By focusing on the immunomodulatory functions of factors secreted by senescent microglia, such as cytokines, chemokines, complement factors, and reactive oxygen species (ROS), we explore the diverse detrimental effects of microglia in aging and AD pathogenesis, including Aβ accumulation, Tau deposition, synaptic dysfunction, and neuroinflammation. These collectively contribute to hastening the progression of. In this review, we highlight the key role of senescent microglia in the pathological processes of AD. Then we propose that targeting senescent microglia holds great promise for therapeutic interventions in neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Microglia senescence; Rejuvenation; Removal of senescent microglia; Restoring the function of senescent microglia
    DOI:  https://doi.org/10.1016/j.brainres.2025.149480
  17. Cell Death Dis. 2025 Jan 14. 16(1): 14
    The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer's disease.
    Xudong Sha, Jiayuan Lin, Kexin Wu, Jia Lu, Zhihua Yu.
      Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer's disease (AD). Here, we report a striking buildup of lipid droplets accumulation in microglia in the 3xTg mouse brain. Moreover, we observed significant upregulation of PKM2 and sterol regulatory element binding protein 1 (SREBP1) levels, which were predominantly localized in microglia of 3xTg mice. PKM2 dimerization was necessary for SREBP1 activation and lipogenesis of lipid droplet-accumulating microglia. RNA sequencing analysis of microglia isolated from 3xTg mice exhibited transcriptomic changes in lipid metabolism, innate inflammation, and phagocytosis dysfunction; these changes were improved with capsaicin-mediated pharmacological activation of TRPV1 via inhibition of PKM2 dimerization and reduction of SREBP1 activation. Lipid droplet-accumulating microglia exhibited increased mitochondrial injury accompanied by impaired mitophagy, which was abrogated upon of TRPV1 activation. Capsaicin also rescued neuronal loss, tau pathology, and memory impairment in 3xTg mice. Our study suggests that TRPV1-PKM2-SREBP1 axis regulation of microglia lipid metabolism could be a therapeutic approach to alleviate the consequences of AD.
    DOI:  https://doi.org/10.1038/s41419-024-07328-8
  18. J Extracell Vesicles. 2025 Jan;14(1): e70041
    Extracellular Vesicles From Bone Marrow-Derived Macrophages Enriched in ARG1 Enhance Microglial Phagocytosis and Haematoma Clearance Following Intracerebral Haemorrhage.
    Libin Hu, Zihang Chen, Jianglong Lu, Shandong Jiang, Haopu Lin, Jiayin Zhou, Ning Wang, Chao Ding, Weifang Ni, Haitao Peng, Yin Li, Xuchao He, Jianru Li, Chaohui Jing, Yang Cao, Hang Zhou, Feng Yan, Gao Chen.
      Microglial phagocytosis of haematomas is crucial for neural functional recovery following intracerebral haemorrhage (ICH), a process regulated by various factors from within and outside the central nervous system (CNS). Extracellular vesicles (EVs), significant mediators of intercellular communication, have been demonstrated to play a pivotal role in the pathogenesis and progression of CNS diseases. However, the regulatory role of endogenous EVs on the phagocytic capacity of microglia post-ICH remains elusive. Utilising multi-omics analysis of brain tissue-derived EVs proteomics and single-cell RNA sequencing, this study identified that bone marrow-derived macrophages (BMDMs) potentially enhance microglial phagocytosis via EVs following ICH. By blocking BMDMs and reducing ARG1 in BMDM-derived EVs, we demonstrated that BMDMs facilitate erythrophagocytosis by delivering ARG1 to microglia via EVs post-ICH. EVs-carried ARG1 was found to augment phagocytosis by promoting RAC1-dependent cytoskeletal remodelling in microglia. Collectively, this research uncovers an intercellular communication pathway from BMDMs to microglia mediated by EVs post-ICH. This provides a novel paradigm for EV-mediated intercellular communication mechanisms and suggests a promising therapeutic potential for BMDM-derived EVs in the treatment of ICH.
    Keywords:  ARG1; BMDM; EVs; ICH; microglia; phagocytosis
    DOI:  https://doi.org/10.1002/jev2.70041
  19. Int J Mol Sci. 2025 Jan 14. pii: 636. [Epub ahead of print]26(2):
    Nobiletin and Eriodictyol Suppress Release of IL-1β, CXCL8, IL-6, and MMP-9 from LPS, SARS-CoV-2 Spike Protein, and Ochratoxin A-Stimulated Human Microglia.
    Irene Tsilioni, Duraisamy Kempuraj, Theoharis C Theoharides.
      Neuroinflammation is involved in various neurological and neurodegenerative disorders in which the activation of microglia is one of the key factors. In this study, we examined the anti-inflammatory effects of the flavonoids nobiletin (5,6,7,8,3',4'-hexamethoxyflavone) and eriodictyol (3',4',5,7-tetraxydroxyflavanone) on human microglia cell line activation stimulated by either lipopolysaccharide (LPS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length Spike protein (FL-Spike), or the mycotoxin ochratoxin A (OTA). Human microglia were preincubated with the flavonoids (10, 50, and 100 µM) for 2 h, following which, they were stimulated for 24 h. The inflammatory mediators interleukin-1 beta (IL-1β), chemokine (C-X-C motif) ligand 8 (CXCL8), IL-6, and matrix metalloproteinase-9 (MMP-9) were quantified in the cell culture supernatant by enzyme-linked immunosorbent assay (ELISA). Both nobiletin and eriodictyol significantly inhibited the LPS, FL-Spike, and OTA-stimulated release of IL-1β, CXCL8, IL-6, and MMP-9 at 50 and 100 µM, while, in most cases, nobiletin was also effective at 10 µM, with the most pronounced reductions at 100 µM. These findings suggest that both nobiletin and eriodictyol are potent inhibitors of the pathogen-stimulated microglial release of inflammatory mediators, highlighting their potential for therapeutic application in neuroinflammatory diseases, such as long COVID.
    Keywords:  CXCL8; IL-1β; IL-6; MMP-9; SARS-CoV-2 spike protein; flavonoids; long COVID; luteolin; mast cells; microglia; neuroinflammation; nobiletin
    DOI:  https://doi.org/10.3390/ijms26020636
  20. J Biophotonics. 2025 Jan 27. e202400482
    Diabetes Mellitus Impairs Blood-Brain Barrier Integrality and Microglial Reactivity.
    Shaojun Liu, Jie Hao, Tingting Yu, Valery V Tuchin, Junming Li, Dongyu Li, Dan Zhu.
      Diabetes mellitus (DM), a chronic metabolic disorder that adversely affects the blood-brain barrier (BBB) and microglial function in the central nervous system (CNS), contributing to neuronal damage and neurodegenerative diseases. However, the underlying molecular mechanisms linking diabetes to BBB dysfunction and microglial dysregulation remain poorly understood. Here, we assessed the impacts of diabetes on BBB and microglial reactivity and investigated its mechanisms. We found diabetes severely disrupted the BBB integrity and microglial response to vascular injury. We also revealed a potential relationship between BBB disruption and impaired microglial function, whereby increasing BBB permeability led to a downregulation of microglial P2RY12 expression, thereby impairing microglial protection against cerebrovascular injury. Understanding these mechanisms may contribute to the developing of therapeutic strategies for diabetes-related neurological complications.
    Keywords:  blood–brain barrier; cerebrovascular injury; diabetes mellitus; microglia
    DOI:  https://doi.org/10.1002/jbio.202400482
  21. Stem Cell Res Ther. 2025 Jan 29. 16(1): 31
    Long non-coding RNA Malat1 modulates CXCR4 expression to regulate the interaction between induced neural stem cells and microglia following closed head injury.
    Qin Dong, Pengyu Chen, Wenqiao Qiu, Zhijun Yang, Yanteng Li, Yuhui Zhou, Lili Guo, Dan Zou, Ruxiang Xu, Mou Gao.
       BACKGROUND: Closed head injury (CHI) provokes a prominent neuroinflammation that may lead to long-term health consequences. Microglia plays pivotal and complex roles in neuroinflammation-mediated neuronal insult and repair following CHI. We previously reported that induced neural stem cells (iNSCs) can block the effects of CXCL12/CXCR4 signaling on NF-κB activation in activated microglia by CXCR4 overexpression. Here we aim to uncover the mechanism of CXCR4 upregulation in iNSCs.
    METHODS: We performed bioinformatic analysis to detect the differentially expressed genes in iNSCs after co-cultured with LPS-activated microglia. Subsequently, we predicted the target genes and performed gain- and loss-of-functional studies, dualluciferase reporter, RNA immunoprecipitation, biotin-coupled miRNA pulldown, fluorescence in situ hybridization and cell transplantation assays to further elucidate the mechanism underlying the immunoregulatory effects of iNSCs. Student's t-test and one-way analysis of variance (ANOVA) with Tukey's post hoc test were used to determine statistical significance.
    RESULTS: Our results indicated that Malat1 could act as a sponge of miR-139-5p to modulate the expression of CXCR4 that exerted significant influence on the immunoregulatory effects of iNSCs on the secretion of CXCL12, TNF-α and IGF-1 by activated microglia. Furthermore, Malat1 inhibition blocked the immunoregulatory effects of iNSC grafts on microglial activation as well as neuroinflammation in the injured cortices of CHI mice. Interestingly, NF-κB activation in iNSCs augmented the immunoregulatory effects of iNSCs on microglial activation by activating the axis of Malat1/miR-139-5p/Cxcr4. Notably, we found that TNF-α secreted by activated microglia could bind to TNFR1 at the surface of iNSCs to trigger NF-κB activation in iNSCs.
    CONCLUSIONS: In short, our findings reveal a novel role of Malat1 in the immunomodulatory effects of iNSCs on microglial activation, suggesting that transplanted iNSCs may self-perceive the changes of the activated state of microglia and thus make prudential regulation of the neuroinflammation following CHI.
    Keywords:   miR-139-5p ; CXCR4; Closed head injury; Induced neural stem cell; Microglia; NF-κB signaling; TNFR1; lncRNA Malat1
    DOI:  https://doi.org/10.1186/s13287-024-04116-1
  22. Adv Sci (Weinh). 2025 Jan 30. e2412556
    Microglia-Derived Interleukin-6 Triggers Astrocyte Apoptosis in the Hippocampus and Mediates Depression-Like Behavior.
    Shi-Yu Shen, Ling-Feng Liang, Tian-Le Shi, Zu-Qi Shen, Shu-Yuan Yin, Jia-Rui Zhang, Wei Li, Wen-Li Mi, Yan-Qing Wang, Yu-Qiu Zhang, Jin Yu.
      In patients with major depressive disorder (MDD) and animal models of depression, key pathological hallmarks include activation of microglia as well as atrophy and loss of astrocytes. Under certain pathological conditions, microglia can inflict damage to neurons and astrocytes. However, the precise mechanisms underlying how activated microglia induced astrocyte atrophy and loss remain enigmatic. In this study, a depression model induced by chronic social defeat stress (CSDS) is utilized. The results show that CSDS induces significant anxiety- and depression-like behaviors, along with notable astrocyte atrophy and apoptosis, microglial activation, and elevated levels of microglial interleukin-6 (IL-6). Subsequent studies demonstrate that IL-6 released from activated microglia promotes astrocyte apoptosis. Furthermore, the knockdown of the P2X7 receptor P2X7 receptor (P2X7R) in microglia, which is implicated in the stress response, reduces stress-induced microglial activation, IL-6 release, and astrocyte apoptosis. Direct inhibition of microglia by minocycline corroborates these effects. The selective knockdown of IL-6 in microglia and IL-6 receptors in astrocytes effectively mitigates depression-like behaviors and reduces astrocyte atrophy. This study identifies microglial IL-6 as a key factor that contributes to astrocyte apoptosis and depressive symptoms. Consequently, the IL-6/IL-6R pathway has emerged as a promising target for the treatment of depression.
    Keywords:  IL‐6; apoptosis; astrocytes; depression; microglia
    DOI:  https://doi.org/10.1002/advs.202412556
  23. Acta Pharmacol Sin. 2025 Jan 29.
    Inhibition of CD36 ameliorates mouse spinal cord injury by accelerating microglial lipophagy.
    Bei-Ni Wang, An-Yu Du, Xiang-Hang Chen, Ting Huang, Abdullah Al Mamun, Ping Li, Si-Ting Du, Yan-Zheng Feng, Lin-Yuan Jiang, Jie Xu, Yu Wang, Shuang-Shuang Wang, Kwonseop Kim, Kai-Liang Zhou, Yan-Qing Wu, Si-Wang Hu, Jian Xiao.
      Spinal cord injury (SCI) is a serious trauma of the central nervous system (CNS). SCI induces a unique lipid-dense environment that results in the deposition of large amounts of lipid droplets (LDs). The presence of LDs has been shown to contribute to the progression of other diseases. Lipophagy, a selective type of autophagy, is involved in intracellular LDs degradation. Fatty acid translocase CD36, a multifunctional transmembrane protein that facilitates the uptake of long-chain fatty acids, is implicated in the progression of certain metabolic diseases, and negatively regulates autophagy. However, the precise mechanisms of LDs generation and degradation in SCI, as well as whether CD36 regulates SCI via lipophagy, remain unknown. In this study, we investigated the role of LDs accumulation in microglia for SCI, as well as the regulatory mechanism of CD36 in microglia lipophagy during LDs elimination in vivo and in vitro. SCI was induced in mice by applying moderate compression on spina cord at T9-T10 level. Locomotion recovery was evaluated at days 0, 1, 3, 7 and 14 following the injury. PA-stimulated BV2 cells was established as the in vitro lipid-loaded model. We observed a marked buildup of LDs in microglial cells at the site of injury post-SCI. More importantly, microglial cells with excessive LDs exhibited elevated activation and stimulated inflammatory response, which drastically triggered the pyroptosis of microglial cells. Furthermore, we found significantly increased CD36 expression, and the breakdown of lipophagy in microglia following SCI. Sulfo-N-succinimidyl oleate sodium (SSO), a CD36 inhibitor, has been shown to promote the lipophagy of microglial cells in SCI mice and PA-treated BV2 cells, which enhanced LDs degradation, ameliorated inflammatory levels and pyroptosis of microglial cells, and ultimately promoted SCI recovery. As expected, inhibition of lipophagy with Baf-A1 reversed the effects of SSO. We conclude that microglial lipophagy is essential for the removal of LDs during SCI recovery. Our research implies that CD36 could be a potential therapeutic target for the treatment and management of SCI.
    Keywords:  CD36; lipid droplets; lipophagy; microglia; spinal cord injury; sulfo-N-succinimidyl oleate sodium
    DOI:  https://doi.org/10.1038/s41401-024-01463-w
  24. Drug Des Devel Ther. 2025 ;19 369-387
    Esketamine at a Clinical Dose Attenuates Cerebral Ischemia/Reperfusion Injury by Inhibiting AKT Signaling Pathway to Facilitate Microglia M2 Polarization and Autophagy.
    Ying Gao, Lu Li, Fang Zhao, Yi Cheng, Mu Jin, Fu-Shan Xue.
       Purpose: This study aimed to assess the protective effect of a clinical dose esketamine on cerebral ischemia/reperfusion (I/R) injury and to reveal the potential mechanisms associated with microglial polarization and autophagy.
    Methods: Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in adult rats and simulated by oxygen-glucose deprivation (OGD) in BV-2 microglial cells. Neurological and sensorimotor function, cerebral infarct volume, histopathological changes, mitochondrial morphological changes, and apoptosis of ischemic brain tissues were assessed in the presence or absence of esketamine and the autophagy inducer rapamycin. The expression of biomarkers related to microglial M1 and M2 phenotypes in the ischemic brain tissues was determined by immunofluorescence staining and RT-qPCR, and the expression of proteins associated with autophagy and the AKT signaling pathway in the ischemic brain tissues was assayed by Western blotting.
    Results: Esketamine alone and esketamine combined with rapamycin alleviated neurological impairment, improved sensorimotor function, decreased cerebral infarct volume, and mitigated tissue injury in the MCAO rats. Importantly, esketamine promoted microglial phenotypic transition from M1 to M2 in both the MCAO rats and the OGD-treated BV-2 microglia, induced autophagy, and inactivated AKT signaling. Furthermore, the effects of esketamine were enhanced by addition of autophagy inducer rapamycin.
    Conclusion: Esketamine at a clinical dose attenuates cerebral I/R injury by inhibiting AKT signaling pathway to facilitate microglial M2 polarization and autophagy. Furthermore, esketamine combined autophagy inducer can provide an improved protection against cerebral I/R injury. Thus, this study provides new insights into the neuroprotective mechanisms of esketamine and the potential therapeutic strategies of cerebral I/R injury.
    Keywords:  autophagy; cerebral ischemia/reperfusion injury; esketamine; ischemic stroke; microglia polarization
    DOI:  https://doi.org/10.2147/DDDT.S504179
  25. Mol Cell Neurosci. 2025 Jan 27. pii: S1044-7431(25)00004-1. [Epub ahead of print]132 103994
    A microglial kinase ITK mediating neuroinflammation and behavioral deficits in traumatic brain injury.
    Ruqayya Afridi, Anup Bhusal, Seung Eun Lee, Eun Mi Hwang, Hoon Ryu, Jong-Heon Kim, Kyoungho Suk.
      Microglia-mediated neuroinflammation has been implicated in the neuropathology of traumatic brain injuries (TBI). Recently, the expression of interleukin-2-inducible T-cell kinase (ITK) has been detected in brain microglia, regulating their inflammatory activities. However, the role of microglial ITK in TBI has not been investigated. In this study, we demonstrate that ITK expression and activation are upregulated in microglia following an injury caused by controlled cortical impact (CCI) - a mouse model of TBI. Pharmacological inhibition of ITK protein or knockdown of microglial ITK gene expression using adeno-associated virus mitigates neuroinflammation and improves neurological outcomes in the CCI model. Additionally, ITK mRNA expression was found to be increased in the brains of patients with chronic traumatic encephalopathy. An ITK inhibitor reduced the activation of inflammatory responses in both human and mouse microglia in vitro. Collectively, these results suggest that microglial ITK plays a pivotal role in neuroinflammation and mediating behavioral deficits following TBI. Thus, targeting the signaling pathway of microglial ITK may exert protective effects by alleviating neuroinflammation associated with TBI.
    Keywords:  Interleukin-2-inducible T-cell kinase; Microglia; Neuroinflammation; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.mcn.2025.103994
  26. Commun Biol. 2025 Jan 17. 8(1): 75
    Prenatal inflammation impairs early CD11c-positive microglia induction and delays myelination in neurodevelopmental disorders.
    Kazuya Fuma, Yukako Iitani, Kenji Imai, Takafumi Ushida, Sho Tano, Kosuke Yoshida, Akira Yokoi, Rika Miki, Hiroyuki Kidokoro, Yoshiaki Sato, Yuichiro Hara, Tomoo Ogi, Kohei Nomaki, Makoto Tsuda, Okiru Komine, Koji Yamanaka, Hiroaki Kajiyama, Tomomi Kotani.
      Histological chorioamnionitis (HCA) is a form of maternal immune activation (MIA) linked to an increased risk of neurodevelopmental disorders in offspring. Our previous study identified neurodevelopmental impairments in an MIA mouse model mimicking HCA. Thus, this study investigated the role of CD11c+ microglia, key contributors to myelination through IGF-1 production, in this pathology. In the mouse model, the CD11c+ microglial population was significantly lower in the MIA group than in the control group on postnatal day 3 (PN3d). Furthermore, myelination-related protein levels significantly decreased in the MIA group at PN8d. In humans, preterm infants with HCA exhibited higher IL-6 and IL-17A cord-serum levels and lower IGF-1 levels than those without HCA, followed by a higher incidence of delayed myelination on magnetic resonance imaging at the term-equivalent age. In silico analysis revealed that the transient induction of CD11c+ microglia during early development occurred similarly in mice and humans. Notably, a lack of high CD11c+ microglial population has been observed in children with neurodevelopmental disorders. This study reports impaired induction of CD11c+ microglia during postnatal development in a mouse model of MIA associated with delayed myelination. Our findings may inform strategies for improving outcomes in infants with HCA.
    DOI:  https://doi.org/10.1038/s42003-025-07511-3
  27. bioRxiv. 2025 Jan 28. pii: 2025.01.19.633810. [Epub ahead of print]
    7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in Alzheimer's disease.
    Kayalvizhi Radhakrishnan, Yiyu Zhang, Oluwaseun Mustapha, Thaddeus K Weigel, Clint M Upchurch, Xiaodong Tian, Franklin Herbert, Wenyuan Huang, Norbert Leitinger, Ukpong Bassey Eyo, Huiwang Ai, Heather A Ferris.
      Oxidative stress is a prominent feature of Alzheimer's disease. Within this context, cholesterol undergoes oxidation, producing the pro-inflammatory product 7-ketocholesterol (7-KC). In this study, we observe elevated levels of 7-KC in the brains of the 3xTg mouse model of AD. To further understand the contribution of 7-KC on the oxidative environment, we developed a method to express a genetically encoded fluorescent hydrogen peroxide (H2O2) sensor in astrocytes, the primary source of cholesterol in the brain. With this sensor, we discovered that 7-KC increases H2O2 levels in astrocytes in vivo, but not when directly applied to astrocytes in vitro. Interestingly, when 7-KC was applied to a microglia cell line alone or mixed astrocyte and microglia cultures, it resulted in microglia activation and increased oxidative stress in astrocytes. Depletion of microglia from 3xTg mice resulted in reduced 7-KC in the brains of these mice. Taken together, these findings suggest that 7-KC, acting through microglia, contributes to increased astrocyte oxidative stress in AD. This study sheds light on the complex interplay between cholesterol oxidation, microglia activation, and astrocyte oxidative stress in the pathogenesis of AD.
    DOI:  https://doi.org/10.1101/2025.01.19.633810
  28. J Neuroinflammation. 2025 Jan 30. 22(1): 23
    Hyperhomocysteinemia-induced VCID results in visual deficits, reduced neuroinflammation and vascular alterations in the retina.
    Erica M Weekman, Colin B Rogers, Tiffany L Sudduth, Donna M Wilcock.
      Over recent years, the retina has been increasingly investigated as a potential biomarker for dementia. A number of studies have looked at the effect of Alzheimer's disease (AD) pathology on the retina and the associations of AD with visual deficits. However, while OCT-A has been explored as a biomarker of cerebral small vessel disease (cSVD), studies identifying the specific retinal changes and mechanisms associated with cSVD are lacking. Using our model of hyperhomocysteinemia-induced cSVD, we aimed to identify the effects of cSVD on visual sensitivity and cognition, retinal glial and vascular cells, and neuroinflammatory and cardiovascular gene expression changes. We placed C57Bl6/SJL mice on a HHcy-inducing diet, a model that has been well characterized to have vascular pathologies in the brain similar to pathologic cSVD. After 14 weeks on diet, mice underwent the Visual-Stimuli 4-arm Maze to identify visual deficits. Whole mount retinas were stained for vessels, microglia and astrocytes to identify glial and vascular changes. Finally, neuroinflammatory and cardiovascular gene expression was measured using NanoString's nCounter system. Ultimately, HHcy led to visual changes that specifically affected the reaction to blue and white light, slightly decreased vascular volume and significantly decreased interaction of microglia with the vasculature, as well as downregulation of inflammatory and vascular genes. These changes provide novel insights and reproduce some prior observations. These studies highlight retinal changes in association with cSVD and serve as a precaution when interpreting vision-dependent cognitive testing of cSVD models.
    Keywords:  Astrocytes; Hyperhomocysteinemia; Microglia; Retina; VCID; Vessels, Vision
    DOI:  https://doi.org/10.1186/s12974-025-03332-7
  29. Nat Commun. 2025 Jan 18. 16(1): 813
    α-Synuclein fibrils enhance HIV-1 infection of human T cells, macrophages and microglia.
    Lia-Raluca Olari, Sichen Liu, Franziska Arnold, Julia Kühlwein, Marta Gil Miró, Ajeet Rijal Updahaya, Christina Stürzel, Dietmar Rudolf Thal, Paul Walther, Konstantin M J Sparrer, Karin M Danzer, Jan Münch, Frank Kirchhoff.
      HIV-associated neurocognitive disorders (HAND) and viral reservoirs in the brain remain a significant challenge. Despite their importance, the mechanisms allowing HIV-1 entry and replication in the central nervous system (CNS) are poorly understood. Here, we show that α-synuclein and (to a lesser extent) Aβ fibrils associated with neurological diseases enhance HIV-1 entry and replication in human T cells, macrophages, and microglia. Additionally, an HIV-1 Env-derived amyloidogenic peptide accelerated amyloid formation by α-synuclein and Aβ peptides. Mechanistic studies show that α-synuclein and Aβ fibrils interact with HIV-1 particles and promote virion attachment and fusion with target cells. Despite an overall negative surface charge, these fibrils facilitate interactions between viral and cellular membranes. The enhancing effects of human brain extracts on HIV-1 infection correlated with their binding to Thioflavin T, a dye commonly used to stain amyloids. Our results suggest a detrimental interplay between HIV-1 and brain amyloids that may contribute to the development of neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-025-56099-z
  30. Front Neurosci. 2024 ;18 1527842
    Mechanisms of vagus nerve stimulation for the treatment of neurodevelopmental disorders: a focus on microglia and neuroinflammation.
    Makenna Gargus, Benneth Ben-Azu, Antonia Landwehr, Jaclyn Dunn, Joseph P Errico, Marie-Ève Tremblay.
      The vagus nerve (VN) is the primary parasympathetic nerve, providing two-way communication between the body and brain through a network of afferent and efferent fibers. Evidence suggests that altered VN signaling is linked to changes in the neuroimmune system, including microglia. Dysfunction of microglia, the resident innate immune cells of the brain, is associated with various neurodevelopmental disorders, including schizophrenia, attention deficit hyperactive disorder (ADHD), autism spectrum disorder (ASD), and epilepsy. While the mechanistic understanding linking the VN, microglia, and neurodevelopmental disorders remains incomplete, vagus nerve stimulation (VNS) may provide a better understanding of the VN's mechanisms and act as a possible treatment modality. In this review we examine the VN's important role in modulating the immune system through the inflammatory reflex, which involves the cholinergic anti-inflammatory pathway, which releases acetylcholine. Within the central nervous system (CNS), the direct release of acetylcholine can also be triggered by VNS. Homeostatic balance in the CNS is notably maintained by microglia. Microglia facilitate neurogenesis, oligodendrogenesis, and astrogenesis, and promote neuronal survival via trophic factor release. These cells also monitor the CNS microenvironment through a complex sensome, including groups of receptors and proteins enabling microglia to modify neuroimmune health and CNS neurochemistry. Given the limitations of pharmacological interventions for the treatment of neurodevelopmental disorders, this review seeks to explore the application of VNS as an intervention for neurodevelopmental conditions. Accordingly, we review the established mechanisms of VNS action, e.g., modulation of microglia and various neurotransmitter pathways, as well as emerging preclinical and clinical evidence supporting VNS's impact on symptoms associated with neurodevelopmental disorders, such as those related to CNS inflammation induced by infections. We also discuss the potential of adapting non-invasive VNS for the prevention and treatment of these conditions. Overall, this review is intended to increase the understanding of VN's potential for alleviating microglial dysfunction involved in schizophrenia, ADHD, ASD, and epilepsy. Additionally, we aim to reveal new concepts in the field of CNS inflammation and microglia, which could serve to understand the mechanisms of VNS in the development of new therapies for neurodevelopmental disorders.
    Keywords:  acetylcholine; microglia; neurodevelopmental disorders; vagus nerve; vagus nerve stimulation
    DOI:  https://doi.org/10.3389/fnins.2024.1527842
  31. J Neuroinflammation. 2025 Jan 14. 22(1): 8
    The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity.
    Daniel Torrente, Enming J Su, Alí Francisco Citalán-Madrid, Gerald P Schielke, Daniel Magaoay, Mark Warnock, Tamara Stevenson, Kris Mann, Flavie Lesept, Nathalie Delétage, Manuel Blanc, Erin H Norris, Denis Vivien, Daniel A Lawrence.
      The thrombolytic protease tissue plasminogen activator (tPA) is expressed in the CNS, where it regulates diverse functions including neuronal plasticity, neuroinflammation, and blood-brain-barrier integrity. However, its role in different brain regions such as the substantia nigra (SN) is largely unexplored. In this study, we characterize tPA expression, activity, and localization in the SN using a combination of retrograde tracing and β-galactosidase tPA reporter mice. We further investigate tPA's potential role in SN pathology in an α-synuclein mouse model of Parkinson's disease (PD). To characterize the mechanism of tPA action in α-synuclein-mediated pathology in the SN and to identify possible therapeutic pathways, we performed RNA-seq analysis of the SN and used multiple transgenic mouse models. These included tPA deficient mice and two newly developed transgenic mice, a knock-in model expressing endogenous levels of proteolytically inactive tPA (tPA Ala-KI) and a second model overexpressing proteolytically inactive tPA (tPA Ala-BAC). Our findings show that striatal GABAergic neurons send tPA+ projections to dopaminergic (DA)-neurons in the SN and that tPA is released from SN-derived synaptosomes upon stimulation. We also found that tPA levels in the SN increased following α-synuclein overexpression. Importantly, tPA deficiency protects DA-neurons from degeneration, prevents behavioral deficits, and reduces microglia activation and T-cell infiltration induced by α-synuclein overexpression. RNA-seq analysis indicates that tPA in the SN is required for the upregulation of genes involved in the innate and adaptive immune responses induced by α-synuclein overexpression. Overexpression of α-synuclein in tPA Ala-KI mice, expressing only proteolytically inactive tPA, confirms that tPA-mediated neuroinflammation and neurodegeneration is independent of its proteolytic activity. Moreover, overexpression of proteolytically inactive tPA in tPA Ala-BAC mice leads to increased neuroinflammation and neurodegeneration compared to mice expressing normal levels of tPA, suggesting a tPA dose response. Finally, treatment of mice with glunomab, a neutralizing antibody that selectively blocks tPA binding to the N-methyl-D-aspartate receptor-1 (NMDAR1) without affecting NMDAR1 ion channel function, identifies the tPA interaction with NMDAR1 as necessary for tPA-mediated neuroinflammation and neurodegeneration in response to α-synuclein-mediated neurotoxicity. Thus, our data identifies a novel pathway that promotes DA-neuron degeneration and suggests a potential therapeutic intervention for PD targeting the tPA-NMDAR1 interaction.
    Keywords:  Dopaminergic neurons; Glunomab; Microglia; NMDAR; Neuroinflammation; Parkinson’s disease; Substantia nigra; T-cell; tPA; α-synuclein
    DOI:  https://doi.org/10.1186/s12974-025-03336-3
  32. Mol Cell Probes. 2025 Jan 27. pii: S0890-8508(25)00009-X. [Epub ahead of print] 102016
    Circulating miR-574-5p shows diagnostic and prognostic significance and regulates oxygen-glucose deprivation (OGD)-induced inflammatory activation of microglia by targeting ATP2B2.
    Xia Yin, Chunlei Zhang.
       BACKGROUND: Early screening is critical for the prevention of ischemic stroke. miR-574-5p was considered a promising biomarker for ischemic stroke but lacks direct confirmation. This study evaluated miR-574-5p in discriminating ischemic stroke and predicting the severity and prognosis of patients, aiming to provide novel insights into the clinical prevention of ischemic stroke.
    METHODS: The clinical significance of miR-574-5p was evaluated in 103 ischemic stroke patients with 87 healthy individuals as control. The potential of serum miR-574-5p in the diagnosis and prognosis of ischemic stroke was assessed by ROC and logistic regression analyses. In vitro, oxygen-glucose deprivation (OGD)-induced microglia was established. The regulation of inflammation, oxidative stress, and proliferation of microglia by miR-574-5p were assessed by cell transfection. The downstream targets of miR-574-5p were predicted from public databases, and the targeting relationship was evaluated by luciferase reporter assay.
    RESULTS: Reducing serum miR-574-5p was observed in ischemic stroke patients relative to healthy individuals, which discriminated ischemic stroke patients. Serum miR-574-5p was negatively correlated with the NIHSS score of ischemic stroke patients and was identified as a risk factor for patients' adverse prognosis. In OGD-induced microglia, overexpressing miR-574-5p could alleviate OGD-induced inflammation and oxidative stress and promote cell growth. Among predicted targets, ATP2B2 was upregulated in ischemic stroke and showed a negative correlation with miR-574-5p. miR-574-5p negatively regulated ATP2B2 in OGD-induced microglia, and the overexpression of ATP2B2 reversed the protective effect of miR-574-5p.
    CONCLUSION: miR-574-5p acted as a biomarker for ischemic stroke and mediated neuroinflammation via targeting ATP2B2.
    Keywords:  biomarker; hypertension; ischemic stroke; microglia; onset; prognosis
    DOI:  https://doi.org/10.1016/j.mcp.2025.102016
  33. Biomolecules. 2024 Dec 26. pii: 16. [Epub ahead of print]15(1):
    IL-18 Blockage Reduces Neuroinflammation and Promotes Functional Recovery in a Mouse Model of Spinal Cord Injury.
    Easmin Begum, Md Rashel Mahmod, Md Mahbobur Rahman, Fumiko Fukuma, Takeshi Urano, Yuki Fujita.
      The prognosis of spinal cord injury (SCI) is closely linked to secondary injury processes, predominantly driven by neuroinflammation. Interleukin-18 (IL-18) plays a pivotal role in this inflammatory response. In previous work, we developed an anti-IL-18 antibody capable of neutralizing the active form of IL-18. This study evaluated the functional effects of this antibody in a mouse model of SCI. IL-18 expression was significantly upregulated in the spinal cord following injury. In a mouse model of SCI (C57BL/6J strain), mice were administered 150 μg of the anti-IL-18 antibody intraperitoneally. IL-18 inhibition via antibody treatment facilitated motor functional recovery post-injury. This intervention reduced neuronal death, reactive gliosis, microglia/macrophage activation, and neutrophil infiltration. Additionally, IL-18 inhibition lowered the expression of pro-inflammatory factors, such as IL-1β and the M1 microglia/macrophage marker Ccl17, while enhancing the expression of the M2 microglia/macrophage marker Arginase 1. Collectively, our findings demonstrate that IL-18 inhibition promotes motor recovery and facilitates the polarization of M1 microglia/macrophages to the M2 phenotype, thereby fostering a neuroprotective immune microenvironment in mice with SCI.
    Keywords:  IL-18; cytokines; gene expression; glia; inflammatory response; neuroinflammation; neuron; neuroprotection; spinal cord injury; traumatic injury
    DOI:  https://doi.org/10.3390/biom15010016
  34. Int J Mol Sci. 2025 Jan 14. pii: 649. [Epub ahead of print]26(2):
    Single-Cell RNA-Seq Uncovers Robust Glial Cell Transcriptional Changes in Methamphetamine-Administered Mice.
    Abiola Oladapo, Uma Maheswari Deshetty, Shannon Callen, Shilpa Buch, Palsamy Periyasamy.
      Methamphetamine is a highly addictive stimulant known to cause neurotoxicity, cognitive deficits, and immune dysregulation in the brain. Despite significant research, the molecular mechanisms driving methamphetamine-induced neurotoxicity and glial cell dysfunction remain poorly understood. This study investigates how methamphetamine disrupts glial cell function and contributes to neurodevelopmental and neurodegenerative processes. Using single-cell RNA sequencing (scRNA-seq), we analyzed the transcriptomes of 4000 glial cell-associated genes from the cortical regions of mice chronically administered methamphetamine. Methamphetamine exposure altered the key pathways in astrocytes, including the circadian rhythm and cAMP signaling; in microglia, affecting autophagy, ubiquitin-mediated proteolysis, and mitophagy; and in oligodendrocytes, disrupting lysosomal function, cytoskeletal regulation, and protein processing. Notably, several transcription factors, such as Zbtb16, Hif3a, Foxo1, and Klf9, were significantly dysregulated in the glial cells. These findings reveal profound methamphetamine-induced changes in the glial transcriptomes, particularly in the cortical regions, highlighting potential molecular pathways and transcription factors as targets for therapeutic intervention. This study provides novel insights into the glial-mediated mechanisms of methamphetamine toxicity, contributing to our understanding of its effects on the central nervous system and laying the groundwork for future strategies to mitigate its neurotoxic consequences.
    Keywords:  astrocytes; methamphetamine; microglia; oligodendrocytes; scRNA sequencing
    DOI:  https://doi.org/10.3390/ijms26020649
  35. Biochim Biophys Acta Mol Cell Res. 2025 Jan 27. pii: S0167-4889(25)00010-2. [Epub ahead of print] 119905
    Serum starvation induces cytosolic DNA trafficking via exosome and autophagy-lysosome pathway in microglia.
    Liyan Zhou, Zilong Wu, Xiaoqing Yi, Dongxue Xie, Jufen Wang, Wenhe Wu.
      The imbalance of microglial homeostasis is highly associated with age-related neurological diseases, where cytosolic endogenous DNA is also likely to be found. As the main medium for storing biological information, endogenous DNA could be localized to cellular compartments normally free of DNA when cells are stimulated. However, the intracellular trafficking of endogenous DNA remains unidentified. In this study, we demonstrated that nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), as the components of endogenous DNA, undergo different intracellular trafficking under conditions of microglial homeostasis imbalance induced by serum starvation. Upon detecting various components of endogenous DNA in the cytoplasmic and extracellular microglia, we found that cytosolic nDNA primarily exists in a free form and undergoes degradation through the autophagy-lysosome pathway. In contrast, cytosolic mtDNA predominantly exists in a membrane-wrapped form and is trafficked through both exosome and autophagy-lysosome pathways, with the exosome pathway serving as the primary one. When the autophagy-lysosome pathway was inhibited, there was an increase in exosomes. More importantly, the inhibition of the autophagy-lysosome pathway resulted in enhanced trafficking of mtDNA through the exosome pathway. These findings unveiled the crosstalk between these two pathways in the trafficking of microglial cytosolic DNA and thus provide new insights into intervening in age-related neurological diseases.
    Keywords:  Cytosolic mtDNA; Cytosolic nDNA; Microglial homeostasis; Serum starvation; Trafficking pathway
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119905
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