bims-microg Biomed News
on Microglia in health and disease
Issue of 2026–09–13
nineteen papers selected by
Marcus Karlstetter, Universität zu Köln
  1. A Lactate-H4K12la-HDAC1 epigenetic axis governs microglial state transitions during experimental autoimmune encephalomyelitis in female mice.
  2. ARID5A RNA-binding coordinates microglial defense and ferroptosis in iPSC-derived models.
  3. Targeting m6A writer METTL3 with engineered nanovesicles reduces neuroinflammation in vitro and in vivo.
  4. Th17 effector cytokines induce shared and distinct microglial and endothelial cell responses in a mouse model for post-streptococcal encephalitis.
  5. Microglial GRB2 is essential for brain ventriculogenesis and CSF homeostasis.
  6. Microglia stabilize sleep homeostasis via adenosine A3 receptor signaling.
  7. Increased Amyloidogenic Neuronal Injury in HIV-1-infected APP-KI Alzheimer's disease mice.
  8. A critical in vivo role for microglial p38α MAPK in HIV-1 associated inflammatory brain injury.
  9. Migrasome-propagated ITGβ3-TGFβ1 circuit orchestrates breast cancer brain metastasis by reprogramming the microglial niche.
  10. SIK3-mKO Enhances Myelin Debris Phagocytosis via CD11c Complement Pathway for White Matter Protection Poststroke.
  11. SERINC2-mediated phosphatidylserine remodeling activates protrusion-localized AXL signaling to promote brain metastasis.
  12. Mismatch negativity matures in adolescence and without sensitivity to microglial depletion.
  13. Integrative transcriptomic analysis reveals KLHL2 downregulation as a potential driver of microglial inflammation in Alzheimer's disease via the WNK3/JNK/c-Jun axis.
  14. Natural microbial enrichment modulates microglial states and transcriptional programs relevant to Alzheimer's disease.
  15. Astrocyte-microglia lactate shuttle restrains microglial phenotypic transition during myelin phagocytosis in radiation-induced brain injury.
  16. Integrated analysis of single-cell and transcriptome data reveals temporal dynamics of microglial phagocytic reprogramming in neuropathic pain progression.
  17. Immune regulation of neuronal stem cells in the medaka retina.
  18. Anti-LAG-3 antibody treatment initiated after symptom onset extends survival in ALS model mice.
  19. Methamphetamine enhances HIV infection of human iPSC-derived microglia.
  1. Nat Commun. 2026 Aug 04. pii: 9593. [Epub ahead of print]17(1):
    A Lactate-H4K12la-HDAC1 epigenetic axis governs microglial state transitions during experimental autoimmune encephalomyelitis in female mice.
    Jiahong Li, Su Meng, Jiajian Li, Quanfeng Wei, Xin Hua, Jinzhou Feng, WenYu Hu, Hongxing Wang, Yinan Zhao.
      Microglial functional plasticity is shaped by metabolic and epigenetic reprogramming, but how these processes regulate central nervous system autoimmunity remains unclear. We find that cerebrospinal fluid lactate levels correlate with multiple sclerosis severity. Using female mouse models of experimental autoimmune encephalomyelitis, spinal lactate accumulation drives persistent microglial histone lactylation, coupling to glycolytic activation. Microglia-specific deletion of lactate dehydrogenase A reduces this lactylation and exacerbates disease severity. Exogenous lactate ameliorates pathology without altering peripheral immune infiltration by suppressing inflammatory states and promoting reparative programs. Epigenomic profiling demonstrates direct lactylation enrichment at promoters of neurotrophic genes, linking metabolic flux to transcriptional activation. Histone deacetylase 1 acts as an epigenetic brake by erasing this modification; its inhibition restores neurotrophic signaling and mitigates pathology. In this work, we show that a lactate-driven epigenetic axis governs microglial state transitions, highlighting a tractable therapeutic target for metabolic intervention in neuroinflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-026-76302-z
  2. Nat Commun. 2026 Aug 12. pii: 9687. [Epub ahead of print]17(1):
    ARID5A RNA-binding coordinates microglial defense and ferroptosis in iPSC-derived models.
    Danielle M Schafer, Steven M Blue, Shuhao Xu, Orel Mizrahi, Maya L Gosztyla, Lena Street, Katherine L Rothamel, Hema Kopalle, Samuel B Landry, Elijah Khalil F Rosales, Rebecca H Tien, Sara Elmsaouri, Nicole G Coufal, Marko Jovanovic, Gene W Yeo.
      RNA-binding proteins (RBPs) are key regulators of gene expression that shape cellular function in health and disease. However, the roles of RBPs in immune cells within the central nervous system (CNS) remain poorly understood. Here, we identify ARID5A as an RBP highly expressed in microglia and uncover its RNA-mediated regulatory functions using integrated multi-omics analyses of its RNA, DNA, and protein interactions. ARID5A regulates the splicing and translation of its RNA targets, many of which are integral to lysosomal, immune, and iron metabolism pathways. We confirm the functional relevance of this ARID5A-dependent RNA regulatory network by demonstrating that ARID5A modulates lysosomal activity, cytokine secretion, iron accumulation, and ferroptosis in iPSC-derived microglia. We further demonstrate that knockdown of microglial ARID5A reduces neuronal ferroptosis in co-cultures, underscoring the interconnected nature of these pathways. Moreover, in microglia harboring the TREM2-T66M mutation, ARID5A depletion restores dysregulated lysosomal and metabolic functions. Our results highlight the importance of protein-RNA interactions in regulating microglial cell biology.
    DOI:  https://doi.org/10.1038/s41467-026-76131-0
  3. Nat Commun. 2026 Aug 08. pii: 9534. [Epub ahead of print]17(1):
    Targeting m6A writer METTL3 with engineered nanovesicles reduces neuroinflammation in vitro and in vivo.
    Liangfu Xu, Yuanwei Pan, Guanjun Li, Peng She, Qian-Fang Meng, Zhigang Liu, Lang Rao.
      Epigenetic editing, particularly N6-methyladenosine (m6A) modification, represents a promising therapeutic strategy by silencing genes without altering DNA sequence. However, in vivo epigenetic intervention of neuroinflammation remains challenging and has rarely been explored. Here we developed a hybrid epigenetic nanomodulator, siMETTL3-hNVs, by integrating natural microglia-derived nanovesicles (NVs) with synthetic liposomes pre-loading small interfering RNA targeting the m6A writer methyltransferase-like 3 (METTL3). Natural NVs enabled siMETTL3-hNVs to achieve inflamed-brain delivery through CCR2-CCL2 chemotaxis and caveolae-mediated transcytosis across the blood-brain barrier. More importantly, relying on abundant cytokine receptors on the NVs, siMETTL3-hNVs served as decoys to neutralize pro-inflammatory cytokines, synergizing with the intracellular silencing of METTL3 to drive microglial M2 repolarization. In female mouse models of acute neuroinflammation and radiation-induced brain injury, siMETTL3-hNVs treatment significantly reduced cytokine levels, attenuated hippocampal damage, and ameliorated cognitive deficits. This work overcomes critical delivery bottlenecks in m6A-based therapeutics and establishes a robust strategy for epigenetic reprogramming of neuroinflammation.
    DOI:  https://doi.org/10.1038/s41467-026-75862-4
  4. Nat Commun. 2026 Aug 11. pii: 9658. [Epub ahead of print]17(1):
    Th17 effector cytokines induce shared and distinct microglial and endothelial cell responses in a mouse model for post-streptococcal encephalitis.
    Charlotte R Wayne, Uğur Akcan, Travis E Faust, Violeta Durán-Laforet, Danny Jamoul, Luca Bremner, Nicole Ampatey, Büşra T Akcan, Sarah J Ho, Bogoljub Ciric, Shannon L Delaney, Wendy S Vargas, Susan Swedo, Vilas Menon, Dorothy P Schafer, Tyler Cutforth, Dritan Agalliu.
      Group A Streptococcus (GAS) infections cause neuropsychiatric complications in children, but the mechanisms linking peripheral infection to brain dysfunction remain unclear. Using mouse genetics, single-cell RNA sequencing, and spatial transcriptomics, we show that GAS infections induce inflammatory transcriptional programs in microglia and brain endothelial cells (BECs), accompanied by loss of blood-brain barrier (BBB) gene expression in female mice. Spatial transcriptomic analyses reveal that GAS-responsive microglia localize near infiltrating CD4+ T cells. Several microglial chemokines induced in mice are elevated in sera from affected patients. Deletion of GM-CSF in CD4⁺ T cells partially reduces microglial chemokine gene expression, without restoring BBB integrity. In contrast, IL-17A neutralization partially rescues BBB transcriptional changes, but not BBB dysfunction, and reduces microglial chemokine expression. Microglia-specific deletion of IL-17 receptor A partially restores BBB integrity after GAS infections. Our findings identify microglial IL-17A-IL17RA signaling as a potential mediator of BBB dysfunction and neuroinflammation after GAS infections.
    DOI:  https://doi.org/10.1038/s41467-026-76232-w
  5. J Clin Invest. 2026 Sep 10. pii: e185791. [Epub ahead of print]
    Microglial GRB2 is essential for brain ventriculogenesis and CSF homeostasis.
    Phan Q Duy, Benjamin C Reeves, Huanxing Sun, Xueyan Peng, Pazhanichamy Kalailingam, Garrett Allington, Evan Dennis, Le Thi Hao, Lei Wang, David Rufino-Ramos, Shujuan Zhao, Qiang Li, Neel H Mehta, William C Davalan, Mason Blacker, Anthony J Piscopo, Shozeb Haider, Baojian Fan, Kedous Y Mekbib, Shuai Shao, Carol Nelson-Williams, TuKiet T Lam, Benjamin P Kleinstiver, Patricia L Musolino, Seth L Alper, Sheng Chih Jin, Erica L Herzog, Kristopher T Kahle.
      Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged cerebrospinal fluid (CSF)-filled ventricles, is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified what we believe to be novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein Growth Factor Receptor-Bound Protein 2 (GRB2) in unrelated patients with CH. GRB2 is significantly co-expressed with one of its known upstream receptor tyrosine kinase partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. Immunoprecipitation validated GRB2-CSF1R binding in mouse microglial cells and human monocyte cell line. Cx3cr1-Grb2fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (non-obstructive) hydrocephalus, mimicking GRB2-mutant patients. The severe ventriculomegaly of Cx3cr1-Grb2fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.
    Keywords:  Genetics; Molecular genetics; Neurodevelopment; Neuroscience
    DOI:  https://doi.org/10.1172/JCI185791
  6. Sci Adv. 2026 Sep 11. 12(37): eaef3957
    Microglia stabilize sleep homeostasis via adenosine A3 receptor signaling.
    Zhong Zhao, Xiaochun Gu, Jing Yu, Xueli Chen, Lifeng Zhang, Ting Zhao, Wei Ye, Heping Cheng.
      Sleep homeostasis maintains the sleep-wake balance through sleep pressure, a process partly orchestrated by the accumulation of extracellular adenosine (eADO). Microglial Ca2+ activity has been implicated in sleep regulation, but the mechanism whereby microglia sense sleep pressure remains unclear. Here, we show that microglia regulate sleep homeostasis through brain state-dependent calcium ion activity driven by adenosine A3 receptor (A3R) signaling. Using miniaturized two-photon microscopy in freely behaving mice, we demonstrate that microglial calcium ion activity is rapidly altered by brain-state transitions. Pharmacological experiments reveal that microglial calcium ion dynamics are predominantly mediated by A3R in response to brain state-dependent eADO oscillations. Microglia-specific deletion of A3R attenuates these state-dependent calcium ion dynamics, impairs microglial morphological plasticity across sleep-wake cycles, and leads to sleep fragmentation by increasing transitions between wakefulness and non-rapid eye movement (NREM) sleep. Together, these findings establish that microglia contribute to sleep homeostasis by stabilizing both wakefulness and NREM sleep, a process partly involving eADO-A3R signaling.
    DOI:  https://doi.org/10.1126/sciadv.aef3957
  7. Alzheimers Dement. 2026 Sep;22(9): e71807
    Increased Amyloidogenic Neuronal Injury in HIV-1-infected APP-KI Alzheimer's disease mice.
    Shaurav Bhattarai, Emma G Foster, Rana Kadry, Yaman Lu, Mohit Kumar, Syed Qasim, Amrita Mitra, Harsh Pathak, Larisa Y Poluektova, Santhi Gorantla, R Lee Mosley, Pravin Yeapuri, Howard E Gendelman.
       INTRODUCTION: A higher incidence of dementia, including Alzheimer's-like pathology, is observed in aged people living with human immunodeficiency virus-1 (HIV-1). However, mechanisms linking HIV-1 to Alzheimer's disease (AD) pathology remain unclear, due to the lack of animal models that allow for concurrent studies of HIV-1 and AD.
    METHODS: We created a novel amyloid precursor protein (APP) (Swedish mutation) knock-in (KI) AD mouse on an immunocompromised NOG background, NOG/APPKM670,671NL/IL-34 (NAIL). Following CD34+ hematopoietic stem cell (HSC) reconstitution, humanized hNAIL mice develop human microglia-like cells in the brain and human immune system in the periphery. This allows, for the first time, studies of progressive brain HIV-1 replication in an AD brain. Four-month-old HSC reconstituted mice were infected with the HIV-1ADA strain, and evaluated at 8 weeks post infection to study the role of brain HIV-1 replication on AD-like pathologies.
    RESULTS: HIV-1 replication increased amyloid-beta (Aβ) load in the brain and reduced synaptic and neuronal integrity. Cell type-specific spatial transcriptomic analysis demonstrated that Aβ and HIV-1 drive distinct transcriptional patterns, whereas dual pathology amplified AD-like pathology. Neurons showed the highest transcriptional change, with genes linked to neuroinflammation, protein trafficking, and synaptic dysfunction.
    DISCUSSION: The hNAIL mice enable interrogation of HIV-AD comorbidities, with a future potential for the development of novel therapeutic interventions.
    Keywords:  APP knock‐in; Alzheimer's disease; HIV‐1; HIV‐associated neurocognitive disorders; amyloid‐beta; disease comorbidities; human microglia; humanized mice; neurodegeneration; neuroinflammation; spatial transcriptomics; synaptic dysfunction
    DOI:  https://doi.org/10.1002/alz.71807
  8. Brain Behav Immun. 2026 Sep 08. pii: S0889-1591(26)00752-X. [Epub ahead of print] 107004
    A critical in vivo role for microglial p38α MAPK in HIV-1 associated inflammatory brain injury.
    Deepika Bhullar, Ricky Maung, Amanda J Roberts, Rabi Murad, Monica J Carson, Marcus Kaul.
      People with HIV (PWH) develop neurocognitive impairment despite control of viral infection. Key pathological features of NeuroHIV patients, including activated microglia, neuronal damage and behavioral impairment, are present in transgenic mice expressing HIV-1 envelope glycoprotein gp120 in their brain (HIVgp120tg). Here we show that microglial mitogen-activated protein kinase p38α plays a crucial in vivo role in neuronal injury triggered by viral gp120. Cre-expression driven by the Cx3cr1 promotor in HIVgp120tg mice with floxed p38α alleles results in deletion of microglial p38α and protection from neuronal injury and behavioral impairment. Moreover, the expression patterns of neurotransmission-related genes differ between gp120-transgenic brains protected from neuronal injury and non-transgenic controls, suggesting that microglial p38α deficiency permits a non-toxic modulation of neurons in the presence of the viral protein. Bulk RNA-seq analysis of murine microglia and follow-up in human microglial cells in which p38α has been knocked out using CRISPR/Cas9 technology using qRT-PCR reveals that deficiency of the kinase leads to a distinct gene expression pattern of reduced inflammatory but preserved anti-viral responses.
    Keywords:  Behavioral deficits; CRISPR/Cas9; Gene expression; HIV; HIV associated neurocognitive disorder; HIVgp120-transgenic; Knockout; Microglia; Neurotoxicity; P38 MAPK
    DOI:  https://doi.org/10.1016/j.bbi.2026.107004
  9. Cancer Biol Med. 2026 Sep 08. pii: j.issn.2095-3941.2025.0803. [Epub ahead of print]
    Migrasome-propagated ITGβ3-TGFβ1 circuit orchestrates breast cancer brain metastasis by reprogramming the microglial niche.
    Song Wang, Xinmiao Xian, Guohao Gu, Jianran Guo, Meng An, Dongbao Li, Qian Wang, Xuefang Huang, Shen Chen, Wei Zhang, Bo Fu.
       OBJECTIVE: The dismal prognosis of breast cancer brain metastasis (BCBM) is attributed to a maladapted tumor microenvironment. This study was aimed at deciphering the role of novel intercellular communicators, tumor-derived migrasomes, in driving BCBM progression, with a focus on their ability to co-opt brain-resident microglia.
    METHODS: Migrasomes were isolated and characterized from brain-tropic (231-BR; Mig-BCBM) and parental breast cancer cells, patient-derived metastatic breast cancer tissues, and mice BCBM tissues. The functional axis was delineated through an integrative approach encompassing proteomics, in vitro co-culture systems, in vivo brain colonization assays, genetic perturbations, and a pharmacological intervention with the clinical-stage TGFβR1 inhibitor galunisertib.
    RESULTS: Mig-BCBM were internalized by microglia, thus triggering their repolarization to a pro-tumorigenic, M2-like state, both in vitro and in vivo. Proteomic profiling identified integrin β3 (ITGβ3) as a key regulator selectively packaged into Mig-BCBM. Mechanistically, migrasomal ITGβ3 activated the PI3K/AKT pathway in microglia, thus driving M2 polarization. These reprogrammed microglia secreted high levels of TGFβ1, which in turn fostered a metastatic niche by inducing Smad2/3-dependent epithelial-mesenchymal transition (EMT) in tumor cells. Crucially, we uncovered a self-amplifying feedforward loop in which microglial-derived TGFβ1 transcriptionally upregulates TSPAN4 via EGR1 in cancer cells, thus enhancing migrasome biogenesis and subsequent ITGβ3 loading. Disrupting this loop with galunisertib potently inhibited BCBM outgrowth and colonization in vivo, without systemic toxicity.
    CONCLUSIONS: This study identified a targetable circuit in BCBM wherein tumor-derived migrasomes, via ITGβ3, engage microglia in a TGFβ1-centered crosstalk. Because this self-reinforcing ITGβ3-TGFβ1 axis sustains the pro-metastatic niche, its disruption might provide a rational therapeutic strategy.
    Keywords:  Breast cancer brain metastasis; ITGβ3; TGFβ1; TSPAN4; microglia; migrasome
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0803
  10. Stroke. 2026 Sep 11.
    SIK3-mKO Enhances Myelin Debris Phagocytosis via CD11c Complement Pathway for White Matter Protection Poststroke.
    Leilei Mao, Chenran Wang, Ke Wang, Chenxi Zhong, Ziyu Shi, Yiwen Yuan, Jianan Zheng, Jingjing Wu, Miao He, Zeyu Sun, Yanqin Gao.
       BACKGROUND: White matter preservation is a rate-limiting factor in neurological recovery after ischemic stroke and depends on efficient clearance of myelin debris by microglia/macrophages. Our prior work demonstrated that microglia/macrophage-specific SIK3 (salt-inducible kinase) knockout (SIK3-mKO) promotes an anti-inflammatory subset, enhances myelin phagocytosis, and limits white matter injury, yet the downstream molecular mechanisms remain undefined. Here, we elucidate a previously unrecognized signaling axis underlying these protective effects.
    METHODS: SIK3-mKO mice (SIK3Flox+/+;CX3CR1CreER) were generated via tamoxifen-induced Cre recombination. Transient focal cerebral ischemia was induced by 60-minute transient middle cerebral artery occlusion. Neurological outcomes were assessed via Garcia, rotarod, foot-fault, and adhesive-removal tests. Immunofluorescence, flow cytometry, single-cell RNA sequencing, real-time quantitative polymerase chain reaction, ex vivo myelin phagocytosis assay, magnetic resonance imaging, and compound action potential recordings were used to characterize microglia/macrophage polarization, myelin phagocytic capacity, white matter integrity, and nerve conduction function.
    RESULTS: In the acute phase poststroke, SIK3-mKO selectively upregulated CD11c and its upstream complement initiator component 1q in anti-inflammatory microglia/macrophage subsets. Within the 400 to 800 µm peri-infarct zone, SIK3-mKO elevated the proportion of CD11c+ microglia/macrophage by 15.1% and C1q+ microglia/macrophage by 15.8% relative to wild-type controls. This CD11c-component 1q axis enhanced myelin debris clearance by 19.0% while constraining pathological engulfment of intact myelin, representing a balanced functional switch that mitigates severe demyelination. Conversely, myeloid-CD11c silencing using AAV-Itgax shRNA partially reversed SIK3-mKO-conferred protection. CD11c knockdown reduced anti-inflammatory microglia/macrophage proportions by 9.7%, attenuated physiological phagocytosis and lowered debris clearance efficiency by 7.5%, reduced MBP (myelin basic protein)-positive myelin preservation by 10.0%, and ultimately impaired white matter preservation and neurological recovery.
    CONCLUSIONS: We identify the SIK3-CD11c-component 1q axis as a novel pathway that orchestrates microglia/macrophage phagocytic homeostasis and preserves white matter integrity after ischemic stroke. These findings clarify SIK3 signaling in microglia/macrophage and highlight the CD11c-centered complement cascade as a promising therapeutic target for restoring white matter integrity in poststroke neurorepair.
    Keywords:  homeostasis; ischemic stroke; macrophages; microglia; phagocytosis
    DOI:  https://doi.org/10.1161/STROKEAHA.126.056423
  11. Cell Rep. 2026 Sep 10. pii: S2211-1247(26)01040-5. [Epub ahead of print]45(9): 117962
    SERINC2-mediated phosphatidylserine remodeling activates protrusion-localized AXL signaling to promote brain metastasis.
    Zhibo Yan, Maja Beus, Zhannan Han, Lihong Pan, Yihui Wang, Junqi Lu, Loren B Weidenhammer, Liang Liu, Spencer Rosario, Jingyun Lee, Cristina M Furdui, Hui-Wen Lo, Eugene S Kandel, Erik J Soderblom, Weili Ma, Qing Chen, Sergei V Kotenko, Raymond B Birge, Mikhail A Nikiforov.
      Cell protrusions (CPs) promote metastasis by coordinating cell invasion, matrix remodeling, and communication with the microenvironment. The receptor tyrosine kinase AXL, activated in brain-tropic metastatic cancers, frequently localizes to CPs. The metabolic cues regulating CP biogenesis and AXL activation remain unclear. Here, we report that in invading cancer cells, phosphatidylserine is the most enriched lipid class in CPs. Mechanistically, we demonstrate that the scramblase-like transmembrane protein SERINC2 functions as a scaffold that interacts with integrins and recruits OSBPL8, an ER-plasma-membrane phosphatidylserine transporter, to CPs. This recruitment leads to phosphatidylserine accumulation and externalization at CPs, activation of CP-localized AXL, and upregulation of cell invasion. Furthermore, extracellular vesicles enriched in phosphatidylserine in a SERINC2-dependent manner stimulate autocrine AXL activation and drive M2-like microglia polarization. Accordingly, SERINC2 enhances orthotopic brain tumor growth and microglial reprogramming in vivo. Our data reveal a SERINC2-OSBPL8 axis orchestrating spatial lipid remodeling, AXL activation, and tumor-microenvironment communication.
    Keywords:  AXL; CP: cancer; CP: cell biology; OSBPL8; SERINC2; brain metastases; breast cancer; cell protrusions; invasion; melanoma; phosphatidylserine
    DOI:  https://doi.org/10.1016/j.celrep.2026.117962
  12. Neuropsychopharmacology. 2026 Sep 12.
    Mismatch negativity matures in adolescence and without sensitivity to microglial depletion.
    Anna M Rader Groves, David A Ricci, Joseph A Wargo, Valentina I Florisel, Hana S Dalwai, Antanovia D Ferrell, Bhoomi Desai, Jordan M Ross, Connor G Gallimore, Chloe L West, Georgia Bastos, Jessica L Bolton, Fumiyasu Imai, Jordan P Hamm.
      Higher brain functions and cognition undergo extensive development during adolescence, when psychiatric disorders such as schizophrenia typically onset. Understanding how developmental processes during adolescence interact with schizophrenia pathophysiology and risk remains a central goal in psychiatry. Here we focus on mismatch negativity, a well-established biomarker of schizophrenia, and show that a key component of mismatch negativity, "deviance detection", emerges during adolescence in mouse primary visual cortex, along with a refinement of fronto-visual functional connectivity. In contrast, we found stimulus-specific adaptation-another component of mismatch negativity-to be present prior to adolescence. Because microglia are implicated in schizophrenia risk and disease states, we further investigated what role microglia may play in the development of mismatch responses under physiological conditions. We found that microglial depletion with PLX5622 in adolescence arrests the development of resting oscillations in frontal areas, but does not affect the development of deviance detection, other signatures of visual context processing, or prefrontal-visual functional connectivity. Our findings suggest (a) a key component of mismatch negativity develops in adolescence, a period of vulnerability to schizophrenia, and (b) the development underlying this component does not require robust microglia activity, clarifying the developmental role of microglia in higher-order visual processing.
    DOI:  https://doi.org/10.1038/s41386-026-02547-3
  13. Neurotherapeutics. 2026 Sep 09. pii: S1878-7479(26)00239-4. [Epub ahead of print]23(5): e01069
    Integrative transcriptomic analysis reveals KLHL2 downregulation as a potential driver of microglial inflammation in Alzheimer's disease via the WNK3/JNK/c-Jun axis.
    Yao Yang, Conghui Dai, Zongtang Xu, Linpei Zhuo, Kun Xiang, Xiaoou Lin, Jing Sun, Jiaming Liu, Qiuling Tong.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by prominent neuroinflammation. Microglia, the resident immune cells of the central nervous system, play a key role in AD-associated neuroinflammation, yet the molecular mechanisms regulating their inflammatory activation remain incompletely understood. In this study, we integrated human single-nucleus RNA sequencing with computational analyses and experimental validation to identify potential regulators of inflammatory microglial states in AD. Microglial subpopulations were characterized, and pseudotime analysis was performed to infer transcriptional state transitions across neuropathological stages. High-dimensional weighted gene co-expression network analysis (hdWGCNA) and machine learning were used to prioritize candidate genes for functional validation. KLHL2 was identified as a candidate regulator, and its expression progressively decreased along the inferred pseudotime trajectory, with concordant decreases in Klhl2 mRNA and KLHL2 protein levels observed in APP/PS1 mice and Aβ42-stimulated BV2 cells. In contrast, WNK3 expression level increased without corresponding changes in Wnk3 mRNA. In BV2 cells, Klhl2 overexpression reduced WNK3 expression level, JNK and c-Jun phosphorylation, and pro-inflammatory mediator expression, whereas Klhl2 knockdown produced the opposite effects. Collectively, these findings support KLHL2 as a negative regulator of microglial inflammatory activation and suggest the involvement of WNK3/JNK/c-Jun signaling in this process.
    Keywords:  Alzheimer’s disease; KLHL2; Microglia; Neuroinflammation; WNK3
    DOI:  https://doi.org/10.1016/j.neurot.2026.e01069
  14. Front Immunol. 2026 ;17 1843174
    Natural microbial enrichment modulates microglial states and transcriptional programs relevant to Alzheimer's disease.
    Mohamed Lala Bouali, Amir Mohamed Kezai, Marc Bazin, Papa Yaya Badiane, Nasim Eskandari, Véronique Lévesque, Justin Robillard, Steeve D Côté, Denis Soulet, Cyntia Tremblay, Frédéric Calon, Françoise Morin, Luc Vallières, Sébastien S Hébert.
       Introduction: The diversity of environmental microbial exposure is a key driver of immune maturation and host defense; however, its impact on brain immunity and neurodegenerative diseases remains poorly documented.
    Methods: Here, we show that controlled indoor rewilding, by introducing a natural farm-like environment into laboratory housing, reshapes peripheral and central nervous system (CNS) immune networks in wild-type (WT) and 5xFAD mice, a model of Alzheimer's disease (AD).
    Results: Compared with traditional specific pathogen-free (SPF) housing, rewilded mice exhibited systemic shifts toward mature immune phenotypes, including increases in effector and memory B and T cells, expansion of antibody-secreting cell subsets, and changes in immunoglobulin isotypes. In the brain, indoor rewilding recalibrated microglial activation of 5xFAD mice, attenuating pro-inflammatory transcriptional programs while enhancing homeostatic, complement, and phagocytic signatures. A strong transcriptional convergence was observed between rewilded and wild mice, with rewilded 5xFAD mice exhibiting greater similarity to human AD transcriptional profiles. Morphological and histochemical analyses confirmed that rewilded microglia adopt metabolically adaptable, homeostatic states that influence amyloid-β plaque binding and clearance.
    Discussion: Collectively, these findings suggest that microbial diversity through "dirty" mouse modeling could enhance the translational relevance of neuroimmunology and neurodegenerative disease research.
    Keywords:  Alzheimer’s disease; microglial states; neurodegenerative diseases; rewilding; transcriptional programs
    DOI:  https://doi.org/10.3389/fimmu.2026.1843174
  15. Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag215
    Astrocyte-microglia lactate shuttle restrains microglial phenotypic transition during myelin phagocytosis in radiation-induced brain injury.
    Rong Li, Anbang Ren, Weirui Chen, Anan Xu, Haifeng Jian, Weilan Zeng, Guixiang Liao, Jie Lin, Yuchao Wu, Ronghui Zheng, Laiji Huang, Kai Liao, Guo Yin, Yawei Yuan.
       Background: Radiation-induced brain injury (RBI) is a serious sequela in long-term survivals of patients with brain tumors or nasopharyngeal carcinoma after receiving radiotherapy. The role of multiple glial cell types in driving major RBI pathologies remains largely unclear.
    Methods: The late-phase radiation response in mouse brain was profiled and analyzed using bulk tissue RNA-sequencing and single-nucleus mRNA sequencing (snRNA-seq). Glia crosstalk was investigated by using primary culture and co-culture.
    Results: We found substantial loss of mature oligodendrocytes and microglia-derived neuroinflammation as 2 major features in late phase of RBI. Loss of oligodendrocytes coincides with the emergence of a radiation-induced reactive microglial subpopulation (RRM_1) characterized by enhanced phagocytosis activity, specialized for myelin debris clearance. Myelin debris phagocytosis induces a M2-to-M1 phenotypic transition in irradiated microglia. Astrocyte-microglia lactate shuttle (AMLS), mediated by monocarboxylate transporters (MCT4/MCT1), suppresses M1-like polarization of microglia. M2-like phenotype could be enhanced by secreted secreted phosphoprotein 1 (SPP1) via boosting AMLS.
    Conclusions: Taken together, we found demyelination and neuroinflammation are two intimately related features in irradiated brain. Microglia and astrocyte collectively contribute to tissue homeostasis by stably scavenging myelin/cellular debris. Our data reveal a correlative glial metabolic cascade (oligodendrocytes, microglia, and astrocytes) linked to chronic neuroinflammation. These findings provide new insights into therapeutic strategies for RBI.
    Keywords:  lactate; monocarboxylate transporter; myelin; phenotype transformation; radiation-induced brain injury
    DOI:  https://doi.org/10.1093/noajnl/vdag215
  16. Sci Rep. 2026 09 07. pii: 27944. [Epub ahead of print]16(1):
    Integrated analysis of single-cell and transcriptome data reveals temporal dynamics of microglial phagocytic reprogramming in neuropathic pain progression.
    Yilun Qian, Yu Wang, Yan Liu, Yao Geng, Manyu Dong, Ying Huang, Chenyuan Zhai, Qinfeng Wu, Shangbo Niu, Wentao Liu, Ying Shen, Qi Wu.
      Neuropathic pain (NP) often progresses from acute to chronic, but the mechanisms driving this transition remain unclear. Microglia play a central role in spinal sensitization, yet their functional evolution during pain chronification is poorly understood. Through integrated multi-omics analysis and experimental validation, this study systematically investigates the temporal dynamics of microglial phagocytic reprogramming during the progression of neuropathic pain (NP). The results demonstrate that in the spared nerve injury (SNI) mouse model, spinal microglia undergo a dynamic evolution across three functional phases: an acute proliferative state with initial phagocytic activation (post-injury day 3, PID3), a transitional phase marked by significant activation of phagocytic pathways (PID7), and a chronic phagocytic "fatigue" state (PID14) in which autophagy- and lysosome-related pathway activity declined with a functional decoupling between phagocytosis and degradative capacity (PID14). Single-cell transcriptomic analysis further revealed functional heterogeneity among microglial subpopulations, including inflammation-regulating subsets (e.g., Micro3/Micro5) and specialized phagocytic clusters (e.g., Clusters 7). Pseudotime trajectory analysis indicated that microglia differentiate from a common progenitor state into two distinct fates: pro-inflammatory or phagocytic. Our analysis at the chronic phase (day 14 post-SNI) confirmed microglial activation, neuroinflammation, and pain hypersensitivity, alongside a novel finding of augmented microglial phagocytosis of apoptotic cells. Further research identified eight phagocytosis-related genes (such as Axl, Mfsd8, Mbtps1, and Sorl1), among which Axl showed the most significant up-regulation in the chronic phase. In vivo and in vitro experiments confirmed that inhibition of Axl not only induced mechanical allodynia but also impaired microglial phagocytic function. Furthermore, under LPS stimulation, microglial phagocytosis exhibited a biphasic response-initial enhancement followed by decline. This work provides new insights into microglial phagocytic reprogramming and suggests Axl as a promising therapeutic target for chronic neuropathic pain.
    Keywords:  Axl; Microglia; Multi-omics analysis; Neuropathic pain; Phagocytosis; Spatiotemporal dynamics
    DOI:  https://doi.org/10.1038/s41598-026-69062-9
  17. Development. 2026 Sep 01. pii: dev205198. [Epub ahead of print]153(17):
    Immune regulation of neuronal stem cells in the medaka retina.
    Rashi Agarwal, Joergen Benjaminsen, Katharina Lust, Clara Julseth, Natalia Fuchs, Eva Hasel de Carvalho, Fanny Eggeler, Omnia El Said Ibrahim, Narges Aghaallaei, Baubak Bajoghli, Joachim Wittbrodt.
      Stem cell populations in tissues require precise regulation of their number and quality to maintain proper organ growth. Among the various regulatory mechanisms, immune cells are emerging to directly regulate stem cell populations. The medaka retinal stem cell (RSC) niche, a model for lifelong neurogenic growth, provides a system for studying immune-stem cell interactions. We investigate how microglia, which are resident macrophages of the central nervous system, regulate the RSC niche. We identify that bona fide RSCs express the chemokine Ccl25b, while its cognate receptor, Ccr9a, is expressed in microglia. These microglia form a surveillance ring adjacent to the RSC niche and actively phagocytose RSCs. Interference with microglia by deletion of spi1b reveals that microglia absence leads to increased numbers of ccl25b-positive RSCs and results in morphological defects of the retina. Targeted mutation of ccl25b specifically affects microglia mobility under injury conditions; however, we did not observe any morphological defects, indicating that Ccl25b-Ccr9a signaling is not essential for stem cell maintenance. Overall, our data show that, under homeostatic conditions, the individual RSCs, which are essential for proper eye development, are actively phagocytosed by immune surveillance.
    Keywords:  Chemokine; Medaka; Microglia; Phagocytosis; Retinal stem cells
    DOI:  https://doi.org/10.1242/dev.205198
  18. Neurosci Res. 2026 Sep 10. pii: S0168-0102(26)00106-9. [Epub ahead of print] 105119
    Anti-LAG-3 antibody treatment initiated after symptom onset extends survival in ALS model mice.
    Yuta Morisaki, Nanaka Nomura, Miruto Matsuda, Motoki Ohshima, Raza Fukuda, Okiru Komine, Takashi Okuda, Koji Yamanaka, Hidemi Misawa.
      Immune checkpoint molecules have emerged as regulators of microglial function in neurodegenerative diseases. We previously demonstrated that LAG-3 shapes disease-associated microglial phenotypes in ALS and that germline LAG-3 deletion in SOD1G93A mice accelerated disease onset but extended duration, leaving survival unchanged. Here, we investigated the therapeutic efficacy of anti-LAG-3 antibody treatment starting after symptom onset. Anti-LAG-3 treatment extended survival, slowed neurological and motor decline, preserved body weight and motor neurons, and reduced microgliosis. Within microglia, the Axl+ phagocytic-module fraction increased while the Dectin-1+ inflammatory-module fraction decreased. These findings indicate that post-onset LAG-3 inhibition is a promising therapeutic strategy for ALS.
    Keywords:  LAG-3; amyotrophic lateral sclerosis; disease-associated microglia; immune checkpoint; microglia; neuroinflammation
    DOI:  https://doi.org/10.1016/j.neures.2026.105119
  19. NeuroImmune Pharm Ther. 2026 Jun 24. 5(2): 265-269
    Methamphetamine enhances HIV infection of human iPSC-derived microglia.
    Xiao-Long Wang, Xu Wang, Yuan Rong, Wen-Zhe Ho.
      Methamphetamine (METH) is a potent psychostimulant that is commonly used by people infected with HIV. Clinically, METH use is implicated in HIV infection and neuroinflammation. In this study, we examined whether METH has direct effect on HIV infection of human microglia, the major target and reservoir cells for the virus in the brain. We observed that METH treatment of human iPSC-derived microglia (iMg) significantly enhanced HIV replication, as indicated by increased HIV gag expression, p24 protein levels, and reverse transcriptase activity. Mechanistically, METH suppressed the expression of interferons (IFNs), IFN stimulated gene (Viperin) and the CC chemokine (RANTES). In addition, METH upregulated the expression of the HIV entry coreceptors (CCR5 and CXCR4) in iMg. These findings suggest that METH use is a promoting factor for HIV infection of microglia. Because many individuals infected with HIV use METH, it is important to further investigate the interactions between METH use and HIV in target cells to better understand the mechanisms underlying HIV persistence in the brain and to develop effective strategies for viral eradication.
    Keywords:  human immunodeficiency virus; induced pluripotent stem cell lines (iPSCs); interferon-stimulated genes; methamphetamine; microglia
    DOI:  https://doi.org/10.1515/nipt-2026-0003
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