bims-microg Biomed News
on Microglia in health and disease
Issue of 2026–10–04
seventeen papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Microglia with distinct origins and non-canonical phenotypes coexist within the border-like niche of the brain's circumventricular organs.
  2. ALKBH5-mediated microglia-neuron crosstalk inhibits sympathetic innervation and adipocyte browning in male mice.
  3. A microglial SPP1-ITGB1 feedback loop sustains thalamic hyperexcitability and post-stroke pain.
  4. A TMEM119-tankyrase axis restrains microglial phagocytosis to maintain memory and enables pharmacological forgetting.
  5. Matrix Rigidity Mechanoprimes Microglia for Inflammation Through Cytoskeletal-to-Nuclear Signaling and 3D Spatio-Epigenomic Remodeling.
  6. H4K12 Lactylation Regulates NDUFS7 to Drive Microglia Reverse Electron Transport in Spinal Cord Injury.
  7. Hypothalamic microglial IL-4 signaling mediates cancer-associated cachexia via sympathetic activation.
  8. Microglial P2Y12 Drives Chronic Cerebral Hypoperfusion via Ca2+ Activity-Mediated Neuroinflammation and Vascular Injury.
  9. Ghrelin Alleviates Aging-Related Cognitive Impairment by Regulating Autophagy-Related Signaling via the SHBG/JNK1/Beclin1 Axis in Microglia.
  10. Targeting Microglial HDAC5 Suppresses NLRP3 Inflammation via NF-κB Deacetylation to Alleviate Ischemic Brain Injury.
  11. Mast Cell-Microglia Crosstalk Drives Aberrant Synaptic Pruning Through PAR-2/MAPK/NF-κB Signaling in Neonatal Hypoxic-Ischemic Encephalopathy.
  12. Hyperglycemia-Induced Microglial CTSS Disrupts Blood-Retinal Barrier Integrity via PAR2-Dependent Downregulation of Endothelial MFSD2A.
  13. Macrophage-Derived, Rather Than Microglial, Cathepsin B Exacerbates Brain Injury After Ischemic Stroke.
  14. West Nile Virus Exploits miR-155-5p-Mediated Regulation of TRIM32-IκBα Axis to Evade NF-κB-Mediated Innate Immune Responses in Human Microglial Cells.
  15. TREM2 Attenuates Microglial Pyroptosis in Sepsis-Associated Encephalopathy Through Modulation of the mtDNA-cGAS-STING Pathway.
  16. Microglia calcium signals drive fine process retraction and promote susceptibility to status epilepticus.
  17. Microglial FKBP51 drives immunometabolic dysfunction linking perioperative neurocognitive disorders and Alzheimer's disease.
  1. Immunity. 2026 Sep 29. pii: S1074-7613(26)00377-8. [Epub ahead of print]
    Microglia with distinct origins and non-canonical phenotypes coexist within the border-like niche of the brain's circumventricular organs.
    Hannah Van Hove, Jonathan Bastos, Daliya Kancheva, Mónica Vara-Pérez, Marie-France Dorion, Frederike Westermann, Can Ulutekin, Hadis Shakeri, Leen Ali, Ayla Line Lievens, Maud Mayoux, Nele Sterczyk, Francesca Biscu, Laura Meysman, Isabelle Scheyltjens, Karen De Vlaminck, Ana Rita Pombo Antunes, Wiebke Mildenberger, Lukas Amann, Diego Gomez-Nicola, Ilse Smolders, Sonia Tugues, Florent Ginhoux, Marco Prinz, Charlotte L Scott, Burkhard Becher, Jo A Van Ginderachter, Melanie Greter, Kiavash Movahedi.
      Circumventricular organs (CVOs) are small brain regions lacking a blood-brain barrier, giving neurons direct access to blood-borne signals, yet how these microenvironments shape the origin and phenotype of local macrophages remains unclear. Using multi-omics, we characterized the immune landscape of two CVOs, the area postrema (AP) and median eminence (ME), revealing brain-border-like environments with a unique macrophage compartment. CVO microglia showed a distinct, heterogeneous phenotype, including a CLEC7Ahigh myelin-associated subset in the ME, shaped by ageing and metabolism. CVO microglia were ontogenically diverse: fetal monocytes entered the CVOs perinatally and generated long-lived monocyte-derived microglia that fully adopted a yolk-sac-derived microglia identity. After depletion, CVO microglia were repopulated by local Sall1high cells but also by monocytes in the AP. Similarly, perivascular CVO border-associated macrophages displayed a distinct phenotype and origin. Our findings establish CVOs as specialized immune niches that shape local macrophages, reflecting the immune and metabolic demands of these environments.
    Keywords:  BAMs; CVO; DAM; area postrema; brain borders; median eminence; microglia; ontogeny
    DOI:  https://doi.org/10.1016/j.immuni.2026.09.002
  2. Nat Commun. 2026 Aug 27. pii: 10297. [Epub ahead of print]17(1):
    ALKBH5-mediated microglia-neuron crosstalk inhibits sympathetic innervation and adipocyte browning in male mice.
    Yong-Feng Yang, Yan Li, Mei-Hua Chen, Xi-De Hu, Yi-Jie Hua, Xiao-Dong Shi, Dong-Hua Hu, Ting Meng, Cheng-Yu Sheng, Tao Zhuang, Cheng-Chao Ruan, Xiang-Rong Zuo, Yu Lei, Ruo-Gu Li.
      Interactions between nervous system and adipose tissue are involved in the regulation of adipocyte browning. However, whether microglial activation participates in the regulation of cold exposure-induced sympathetic innervation and adipocyte browning is unclear. Here, we demonstrate that RNA m6A demethylase ALKBH5 in the microglia nucleus of hypothalamus (PVH) region inhibits cold exposure-induced adipocyte browning in the subcutaneous white adipose tissue (sWAT) of male mice. The single nuclear-RNA sequencing, brain slice electrophysiological assay and pathological analyses show that microglia-specific ALKBH5 knockout (MCKO) enhances sympathetic activation and adipocyte browning in the sWAT during cold exposure. Mechanistically, MCKO enhances m6A methylation of Ntf5 mRNA and upregulates Ntf5 expression in the microglia. Ntf5 then activates PVH-TrkB neurons and downstream sympathetic innervation in the sWAT. During aging, MCKO prevents brown adipocyte decline in the sWAT, and promotes metabolic activity. These findings fill a gap in the research of microglia in neuron-mediated adipocyte browning, and suggest that microglia may be a potential therapeutic target for the treatment of individuals with metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-026-77050-w
  3. Neuron. 2026 Sep 28. pii: S0896-6273(26)00679-3. [Epub ahead of print]
    A microglial SPP1-ITGB1 feedback loop sustains thalamic hyperexcitability and post-stroke pain.
    Ruicheng Dai, Wenting Wu, Xiangyu Zhou, Yu Zhou, Xinwei Gao, Minmin Luo.
      Central post-stroke pain (CPSP) represents a failure of homeostatic recovery, yet how acute injury transitions to chronic pain remains elusive. While glial reactivity is a hallmark of stroke, the effectors translating this activation into sustained neuronal hyperexcitability are undefined. Here, we identify microglia-derived secreted phosphoprotein 1 (SPP1) as a key chronification switch for CPSP-like behaviors in mice. Hemorrhage-induced ATP release activates P2X7 receptors, triggering robust SPP1 expression in microglia. This engages a self-amplifying, autocrine integrin β1 (ITGB1) signaling loop that perpetuates a chemokine-rich, pro-nociceptive milieu. Optogenetic activation of this microglial state is sufficient to induce mechanical allodynia and thalamic hyperexcitability without injury. Genetic and pharmacological dissections reveal a critical temporal dissociation: while SPP1 is induced acutely, its signaling via ITGB1 is specifically required to maintain chronic pain. These findings define the SPP1-ITGB1 axis as a fundamental driver of maladaptive sensory plasticity and a promising therapeutic target for refractory central pain.
    Keywords:  P2X7 receptor; chemokines; mechanical allodynia; neuropathic pain; optogenetics; osteopontin; scRNA-seq; thalamic hemorrhage
    DOI:  https://doi.org/10.1016/j.neuron.2026.08.028
  4. Neuron. 2026 Sep 30. pii: S0896-6273(26)00684-7. [Epub ahead of print]
    A TMEM119-tankyrase axis restrains microglial phagocytosis to maintain memory and enables pharmacological forgetting.
    Suhua Sun, Chenfeng Wang, Yang Bian, Ming Hao, Jiacheng Wei, Ronghao Tang, Xi Wu, Huanhuan Wang, Bo Liu, Lisang Zhong, Zhiwei You, Jianbin Wang, Hai Qi.
      The persistence or loss of memory depends on the stability of synaptic connections. Microglia regulate this stability in part by phagocytic elimination of synapses, while the molecular mechanism that sets their intrinsic phagocytic capacity at homeostasis remains unknown. Here, we show that TMEM119, a microglia-specific transmembrane protein, functions as a constitutive cell-intrinsic brake on microglial surveillance dynamics and phagocytosis. Mechanistically, TMEM119 sequesters tankyrase, preventing axin degradation, thereby limiting the pool of free adenomatous polyposis coli protein available to nucleate actin assembly and drive phagocytosis. In adult mice, acute ablation of TMEM119 from microglia exaggerates synapse elimination and destabilizes established fear memories. These effects are recapitulated by a membrane-permeable peptide that enters microglia in the brain after intravenous delivery to competitively disrupt TMEM119-tankyrase association. Our results identify the TMEM119-tankyrase-axin axis as a pharmacologically accessible rheostat of microglial phagocytosis and establish a new framework for memory manipulation.
    Keywords:  TMEM119; memory; microglia; phagocytosis; synapse; tankyrase
    DOI:  https://doi.org/10.1016/j.neuron.2026.09.001
  5. Adv Sci (Weinh). 2026 Sep 27. e77736
    Matrix Rigidity Mechanoprimes Microglia for Inflammation Through Cytoskeletal-to-Nuclear Signaling and 3D Spatio-Epigenomic Remodeling.
    Yu Xuan Meng, Jaegeon Joo, Yu Meng Li, Cheng Ji Li, Ali Taghizadeh, Seung Jae Shin, Buuvee Bayarkhangai, Tae-Woo Ha, Sak Lee, Jaewoo Chung, Bo-Eun Yoon, Hye Sung Kim, Inkyung Jung, Jung-Hwan Lee, Kam W Leong, Hae-Won Kim.
      Microglia play a pivotal role in modulating the pathophysiology of the central nervous system, including disease progression and injury repair. While the biochemical factors governing microglial activation are well understood, the impact of biophysical cues, such as extracellular matrix (ECM) mechanics, remains largely unexplored. Here, we demonstrate how matrix rigidity mechanoprimes microglia for inflammation through coordinated cytoskeletal-to-nuclear signaling and 3D spatio-epigenomic remodeling. In response to rigid matrices, microglia undergo progressive actin cytoskeletal remodeling, morphological adaptation, and nuclear deformation. ATAC-seq reveals that rigidity redistributes rather than globally increases chromatin accessibility: most differentially accessible regions lose accessibility, whereas a defined subset gains focal accessibility at inflammation-associated loci, establishing a permissive state for subsequent activation. Upon LPS challenge, rigidity amplifies inflammatory responses through NF-κB activation and cytoskeleton-dependent MRTF-A nuclear translocation. Integrating ChIP-seq and Hi-C identifies rigidity-responsive cis-regulatory elements (mechanoCREs) and shows that rigidity promotes long-range chromatin interactions linking distal mechanoCREs to inflammatory genes. Together, these findings establish ECM rigidity as a key regulator of microglial inflammation by coupling actin-mediated mechanotransduction to chromatin accessibility and higher-order genome organization, providing a mechanistic basis for mechanically amplified neuroinflammation.
    Keywords:  chromatin accessibility; matrix rigidity; mechanoCREs; microglia; neuroinflammation
    DOI:  https://doi.org/10.1002/advs.77736
  6. Adv Sci (Weinh). 2026 Sep 29. e78057
    H4K12 Lactylation Regulates NDUFS7 to Drive Microglia Reverse Electron Transport in Spinal Cord Injury.
    Chenglong Hong, Zhichen Jiang, Zhouwei Wu, Chenyu Wu, Jiang Liu, Kaijie Guo, Yihui Liang, Shaobo Xu, Yuchen Jin, Yong Xiao, Lei Guo, Hui Xu, Sunren Sheng, Chenggui Wang.
      Microglial polarization toward the pro-inflammatory state drives secondary injury following spinal cord injury (SCI), yet the mechanisms of metabolic reprogramming governing this phenotypic shift remain elusive. Here, we identify a lactate-dependent signaling axis linking histone lactylation to mitochondrial reverse electron transport (RET) that sustains neuroinflammation. We demonstrate that SCI-induced accumulation of lactate promotes histone H4 lysine 12 lactylation (H4K12la), which directly upregulates NDUFS7, a core subunit of mitochondrial Complex I. Elevated NDUFS7 triggers mitochondrial hyperactivity and RET, resulting in a reactive oxygen species (ROS) burst that enforces pro-inflammatory polarization. To intervene in this cascade, we engineered a biomimetic nanotherapeutic, MM@mPTC, comprising an LDHA-targeting PROTAC encapsulated within ROS-responsive micelles and coated with microglial membranes (MM). The biomimetic MM@mPTC system actively targets activated microglia and undergoes ROS-responsive payload release to specifically degrade LDHA. This targeted degradation dismantles the pathogenic "LDHA-H4K12la-NDUFS7-RET" axis, halting RET-driven ROS production and reprogramming microglia toward a reparative phenotype. Consequently, this intervention significantly mitigates neuroinflammation, preserves neuronal tissue, and promotes robust locomotor recovery, presenting a precise metabolic-epigenetic therapeutic paradigm for central nervous system trauma.
    Keywords:  LDHA; NDUFS7; PROTAC; histone lactylation; reverse electron transport; spinal cord injury
    DOI:  https://doi.org/10.1002/advs.78057
  7. Metabolism. 2026 Sep 27. pii: S0026-0495(26)00302-1. [Epub ahead of print] 156789
    Hypothalamic microglial IL-4 signaling mediates cancer-associated cachexia via sympathetic activation.
    Saeha Kim, Sooyeon Jang, Songyi Park, Subin Moon, Yejin Park, Dan-Gyeong Song, Dae-Chul Shin, Jieun Kang, Seung Eun Lee, Dongbum Kim, Jong-Hee Sohn, Keunwook Lee, Ki Woo Kim, Min-Seon Kim, Chan Hee Lee.
       BACKGROUND: Cancer-associated cachexia (CAC) is a debilitating metabolic syndrome characterized by progressive adipose tissue and skeletal muscle wasting. Emerging evidence implicates the central nervous system (CNS) as a key regulator of systemic catabolism and CAC progression. We identify interleukin-4 (IL-4) as a potential mediator of CAC by investigating its actions on hypothalamic neuroendocrine circuits.
    METHODS: We manipulated central IL-4 signaling in CAC mice through intracerebroventricular (ICV) delivery of anti-IL-4 antibody or recombinant IL-4. Hypothalamic cell type-specific IL-4 mechanisms were examined using CX3CR1-creERT2 mice for microglial IL-4 receptor (IL-4R) knockdown and pro-opiomelanocortin (POMC)-cre mice for chemogenetic modulation of POMC neurons. IL-4-induced neuroglial interactions were assessed using BV2 microglial and mHypoE-N1 hypothalamic neuronal cell lines and primary cells.
    RESULTS: Serum IL-4 and hypothalamic phospho-STAT6 were markedly elevated in tumor-bearing mice. Central IL-4 blockade significantly attenuated adipose tissue and muscle wasting, whereas ICV IL-4 administration reproduced cachectic phenotypes, establishing a causal role for brain IL-4 signaling in CAC. Central IL-4 drove adipose and muscle catabolism by activating two mechanistically distinct pathways: sympathetic nervous system and hypothalamic-pituitary-adrenal axis. IL-4R expression was predominantly localized to microglia, and IL-4-activated hypothalamic microglia engaged POMC neurons through proximity-dependent neuroglial interactions. Conditional knockdown of microglial IL-4R or chemogenetic suppression of POMC neurons markedly ameliorated tumor-induced cachexia, defining a central IL-4-microglia-POMC axis that contributes to the catabolic program in CAC.
    CONCLUSIONS: Hypothalamic IL-4 signaling contributes to CAC-associated tissue wasting and highlights microglial IL-4 signaling or POMC modulation as a potential mechanistic target for future therapeutic investigation.
    Keywords:  Cancer-associated cachexia; Hypothalamic microglia; Interleukin-4; Pro-opiomelanocortin neurons; Sympathetic nervous system
    DOI:  https://doi.org/10.1016/j.metabol.2026.156789
  8. Stroke. 2026 Sep 28.
    Microglial P2Y12 Drives Chronic Cerebral Hypoperfusion via Ca2+ Activity-Mediated Neuroinflammation and Vascular Injury.
    Qiankang Chen, Shihao Yuan, Yana Wang, Jiaying Li, Xingdong Chen, Zengyu Zhang, Ziyu Shi, Yiwen Yuan, Leilei Mao, Yuzhen Xu, Zeyu Sun, Yanqin Gao.
       BACKGROUND: Chronic cerebral hypoperfusion is a major driver of vascular cognitive impairment (VCI), but the role of microglial purinergic signaling in chronic cerebral hypoperfusion-induced neurovascular dysfunction remains undefined. This hypothesis-testing study with a novel research premise aimed to address this knowledge gap by clarifying whether microglial P2Y12 (purinergic receptor P2Y12), a microglia-enriched G-protein-coupled receptor, mediates VCI pathogenesis through regulation of microglial calcium signaling and microglia-vascular crosstalk under chronic cerebral hypoperfusion conditions.
    METHODS: VCI was induced in adult male mice by asymmetrical bilateral carotid artery stenosis. Microglia-specific P2Y12 knockout mice were generated using P2Y12flox/flox:CX3CR1CreER mice. Cognitive function was assessed by object location recognition, 3-chamber social interaction, and Morris water maze tests. Cerebral blood flow was measured by laser speckle contrast imaging and functional ultrasound. Neuroinflammation, microvascular integrity, and perivascular microglial Ca2+ activity were evaluated by immunofluorescence, flow cytometry, and 2-photon GCaMP6f imaging. The clinically approved L-type Ca2+ channel blocker nimodipine was administered starting 42 days postasymmetrical bilateral carotid artery stenosis.
    RESULTS: All experimental animals exhibited consistent baseline physiological and behavioral status without intergroup differences throughout the procedure. Chronic cerebral hypoperfusion induced persistent upregulation of P2Y12 in hippocampal microglia. Microglial P2Y12 genetic ablation effectively ameliorated hypoperfusion-triggered cognitive impairment, hippocampal atrophy, and neuronal loss, preserved cerebral perfusion, and inhibited sustained microglial inflammatory activation and pathological microglia-microvessel interaction. Mechanistically, P2Y12 signaling mediated aberrant ATP-triggered Ca2+ hyperactivity in perivascular microglia, and this pathological phenotype was eliminated by microglial P2Y12 deletion. Pharmacological intervention with nimodipine recapitulated the protective effects of genetic P2Y12 inhibition, normalizing abnormal microglial calcium activity, alleviating neuroinflammation and disruptive microglia-vascular crosstalk, maintaining cerebral structural and perfusion homeostasis, and rescuing cognitive dysfunction in model mice, while exerting no adverse effects on control animals.
    CONCLUSIONS: The microglial P2Y12/Ca2+ axis is a critical pathogenic driver of chronic cerebral hypoperfusion-induced VCI, linking sustained microglial activation to neuroinflammation and cerebral microvascular injury. Pharmacological inhibition of this axis with nimodipine recapitulates the benefits of genetic P2Y12 deletion, identifying a clinically translatable therapeutic strategy for VCI treatment. All conclusions are fully supported by the comprehensive behavioral, imaging, and molecular experimental results obtained in this study.
    Keywords:  calcium; cognition; neuroinflammatory diseases; nimodipine; perfusion
    DOI:  https://doi.org/10.1161/STROKEAHA.126.056302
  9. Aging Cell. 2026 Oct;25(10): e70732
    Ghrelin Alleviates Aging-Related Cognitive Impairment by Regulating Autophagy-Related Signaling via the SHBG/JNK1/Beclin1 Axis in Microglia.
    Lixing Zhou, Ying Cheng, Wanyu Zhao, Xuelian Sun, Fengjuan Hu, Meiling Ge, Yan Zhang, Gongchang Zhang, Birong Dong, Xiaolei Liu.
      Cognitive impairment (CI) associated with aging and immunosenescence is linked to metabolic alterations. Microglial senescence and dysregulated autophagy have been implicated as major contributors to this process, but the underlying metabolic regulators remain unclear. This study aimed to identify key metabolic regulators of CI and elucidate their underlying mechanisms. Human cohort analyses, older and D-galactose (D-gal)-induced mouse models, and microglial cell models were integrated to investigate the metabolic regulation of CI. Clinical analyses identified ghrelin as the factor most strongly associated with CI. Older and D-gal mice exhibited CI, microglial senescence, enhanced inflammation, and elevated ghrelin. Ghrelin treatment improved cognitive function, attenuated microglial senescence, and suppressed inflammation, whereas high-dose ghrelin induced growth hormone secretagogue receptor (GHSR) desensitization. Sex hormone-binding globulin (SHBG) showed mainly cytoplasmic localization, was identified as a potential mediator of ghrelin signaling in microglia, and its expression was downregulated following ghrelin treatment. Transcriptomic profiling revealed significant enrichment of autophagy-related pathways in ghrelin-treated microglia. Ghrelin altered autophagy-related markers, as indicated by increased Beclin1 and LC3 and decreased p62. SHBG overexpression or JNK1 inhibition attenuated the ghrelin-induced alterations in autophagy-related markers and anti-senescent effects, whereas Beclin1 overexpression partially rescued these inhibitory effects caused by SHBG overexpression. In conclusion, ghrelin alleviated aging-related CI, with mechanistic evidence indicating that the modulation of microglial autophagy-related mechanisms through the SHBG/JNK1/Beclin1 axis may contribute to its protective effects, thereby providing a potential therapeutic strategy for aging-related CI.
    Keywords:  autophagy; cognitive impairment; ghrelin; immunosenescence
    DOI:  https://doi.org/10.1111/acel.70732
  10. CNS Neurosci Ther. 2026 Oct;32(10): e71161
    Targeting Microglial HDAC5 Suppresses NLRP3 Inflammation via NF-κB Deacetylation to Alleviate Ischemic Brain Injury.
    Ru-Yu Liang, Jia-Qi Zhang, Tian-Yi Jiang, Li-Qing Tao, Wen She, Zhou-Na Sun, Cui Qi, Jun Gao.
       OBJECTIVE: Histone deacetylases are implicated in ischemic stroke, yet the role of HDAC5 remains poorly defined. This study aimed to determine the pathological significance of HDAC5 after cerebral ischemia, clarify its involvement in post-ischemic NF-κB p65/NLRP3 signaling, and evaluate an HDAC5-targeted extracellular vesicle (EV)-based therapeutic strategy.
    METHODS: HDAC5 expression after ischemic injury was examined in a mouse middle cerebral artery occlusion (MCAO) model by western blotting and immunofluorescence. Its function was assessed by gain- and loss-of-function experiments in BV2 cells and MCAO mice. Infarct volume, cerebral blood flow, and neurological recovery were evaluated by TTC staining, magnetic resonance imaging (MRI), color Doppler imaging, and behavioral tests. Co-immunoprecipitation, acetylation analysis, and cytoplasmic/nuclear fractionation were used to explore the underlying mechanism. Human neural stem cell-derived EVs loaded with miR-9-5p and modified with RGD peptide were further tested as a targeted therapeutic approach.
    RESULTS: HDAC5 was markedly upregulated after MCAO, localizing mainly to neurons in the ischemic core and microglia in the penumbra, together with increased NLRP3 expression. In BV2 cells, HDAC5 overexpression increased NLRP3 expression, whereas HDAC5 knockdown reduced it. In vivo, AAV-mediated HDAC5 knockdown decreased NLRP3 levels, reduced infarct volume, improved blood flow recovery, and ameliorated motor deficits after MCAO. Mechanistically, HDAC5 interacted with NF-κB p65 rather than NLRP3. HDAC5 knockdown increased p65 acetylation and reduced its nuclear translocation, consistent with suppression of NLRP3-associated inflammatory signaling. Moreover, engineered RGD-EV:miR-9-5p was efficiently taken up by microglia, suppressed HDAC5 and NLRP3 expression, and improved histological and functional outcomes after MCAO.
    CONCLUSION: These findings identify HDAC5 as a previously underappreciated regulator of post-ischemic inflammatory injury and support a role for the HDAC5/NF-κB p65/NLRP3 axis in cerebral ischemia. Engineered RGD-EV:miR-9-5p may therefore represent a promising targeted therapeutic strategy for ischemic stroke.
    Keywords:  HDAC5; NLRP3; extracellular vesicles; ischemic stroke; targeted delivery
    DOI:  https://doi.org/10.1002/cns.71161
  11. CNS Neurosci Ther. 2026 Oct;32(10): e71189
    Mast Cell-Microglia Crosstalk Drives Aberrant Synaptic Pruning Through PAR-2/MAPK/NF-κB Signaling in Neonatal Hypoxic-Ischemic Encephalopathy.
    Yanping Yang, Dingliang Cai, Jingwen Yu, Yixiao Zhu, Yongxin Huang, Yubing Lin, Chengqian Teng, Jianjie Wei, Ying Lin, Dongsheng Dai, Fushan Xue, Andi Chen, Xiaochun Zheng, Xiaohui Chen.
       AIMS: Neonatal hypoxic-ischemic encephalopathy (HIE) causes severe neurodevelopmental impairment, but the upstream immune mechanisms that initiate this process remain unclear. We investigated whether mast cell (MC)-derived tryptase contributes to aberrant microglia-mediated synaptic pruning through PAR-2/MAPK/NF-κB signaling after neonatal hypoxic-ischemic (HI) injury.
    METHODS: A postnatal Day-7 rat HI model was established using the Rice-Vannucci method. MC abundance, c-Kit and tryptase expression, PAR-2/MAPK/NF-κB signaling, and synaptic integrity were assessed using histological, immunofluorescence, biochemical, ultrastructural, and three-dimensional (3D) reconstruction analyses. Microglia-targeted F2rl1 silencing and pharmacological inhibition with FSLLRY-NH2 or APC366 were used to examine PAR-2 and tryptase-related signaling. Complementary oxygen-glucose deprivation/reperfusion (OGD/R) experiments were performed in BV-2 microglia. Cognitive outcomes were assessed using the Morris water maze and Y maze.
    RESULTS: HI increased hippocampal MC abundance and tryptase expression, and these changes were associated with acute neurological deficits. HI insult also increased complement associated synaptic labeling, PAR-2/MAPK/NF-κB signaling, CD68 expression, and engulfment of PSD95 positive synaptic material. Microglia-targeted F2rl1 silencing attenuated pathway activation and synaptic engulfment. FSLLRY-NH2 and APC366 similarly reduced HI associated signaling and microglial synaptic engulfment, while APC366 preserved dendritic spine density and synaptic ultrastructure and improved long-term spatial learning and memory. In BV-2 microglial cells, exogenous tryptase enhanced OGD/R associated CD68 expression and MAPK/NF-κB phosphorylation, which were attenuated by F-NH2.
    CONCLUSION: MC-derived tryptase is an upstream contributor to pathological microglial synaptic pruning and cognitive impairment after neonatal HI, potentially involving the PAR-2/MAPK/NF-κB axis.
    Keywords:  hypoxic–ischemic; mast cell; synaptic pruning; tryptase
    DOI:  https://doi.org/10.1002/cns.71189
  12. CNS Neurosci Ther. 2026 Oct;32(10): e71187
    Hyperglycemia-Induced Microglial CTSS Disrupts Blood-Retinal Barrier Integrity via PAR2-Dependent Downregulation of Endothelial MFSD2A.
    Chengye Xu, Hongxue Li, Qian Xu, Kangqi Zhao, Yangwen Chen, Yan Wang, Wei Zou, Binglin Kuang, Hongyu Kuang.
       BACKGROUND: Diabetic retinopathy (DR), a leading cause of blindness in diabetes, involves dysregulated neuroimmune crosstalk. While microglial activation and endothelial dysfunction are established in DR, the molecular mechanisms linking innate immunity to blood-retinal barrier (BRB) breakdown remain elusive.
    METHODS: We combined single-cell RNA sequencing (scRNA-seq) of diabetic mouse retinas with in vivo models, retinal endothelial MFSD2A overexpression, and microglial Cathepsin S (CTSS) knockdown via adeno-associated virus (AAV). Human retinal microvascular endothelial cells (HRMECs) and human microglial cells (HMC3) were subjected to high-glucose conditions combined with in vitro systems (transwell co-cultures, holographic 3D tomography). Mechanistic studies employed siRNA knockdown, plasmid overexpression, exogenous CTSS supplementation, and transcytosis assays.
    RESULTS: scRNA-seq revealed diabetes-induced CTSS upregulation in retinal microglia (p = 0.0031) and MFSD2A downregulation in endothelial cells (p = 0.01). Microglial CTSS promoted M1 polarization (p < 0.001) and pro-inflammatory cytokine secretion (IL-1β and TNF-α, p < 0.05), while Ctss knockdown attenuated these effects (p < 0.05). CTSS activated endothelial PAR2, suppressing endothelial MFSD2A and enhancing caveolin-1-mediated transcytosis. Endothelial MFSD2A overexpression reduced vascular permeability independently of tight junction modulation (ZO-1, Occludin, Claudin-5, p > 0.05). Microglia-endothelial crosstalk was disrupted in diabetes, with ultrastructural alterations (cytoplasmic shrinkage, microglial amoeboid transformation) promoting cytotoxic interactions and exacerbate vascular endothelial damage.
    CONCLUSIONS: Hyperglycemia induces retinal microglial activation and CTSS upregulation, disrupting microglia-endothelial crosstalk via the PAR2 pathway, suppressing endothelial MFSD2A expression, enhancing transcytosis, compromising iBRB integrity, and accelerating DR progression. Therapeutic strategies targeting microglial CTSS or endothelial MFSD2A represent promising avenues for preserving vision in diabetic patients.
    Keywords:  Cathepsin S; diabetic retinopathy; endothelial cells; major facilitator superfamily domain‐containing protein 2a; microglia
    DOI:  https://doi.org/10.1002/cns.71187
  13. Glia. 2026 Dec;74(12): e70228
    Macrophage-Derived, Rather Than Microglial, Cathepsin B Exacerbates Brain Injury After Ischemic Stroke.
    Wei Kong, Hui Li, Zhou Wu, Yoshinori Hayashi, Hiroshi Nakanishi, Juan Zhao, Yutong Zhang, Hong Qing, Zhenzhen Quan, Junjun Ni.
      Neuroimmune responses critically shape the progression and outcome of ischemic stroke, yet the cell type-specific roles of myeloid populations remain incompletely defined. Cathepsin B (CatB), a lysosomal cysteine protease, has been implicated in neuroinflammation, but its contribution from distinct myeloid subsets is unclear. Transient middle cerebral artery occlusion (tMCAO) was induced in wild-type and CatB-deficient mice. Bone marrow chimeras were generated to selectively delete CatB in peripheral myeloid cells or resident microglia. Infarct severity, mortality, myeloid phenotypes, and transcriptional programs were assessed using flow cytometry, immunofluorescence, and bulk and cell type-resolved RNA sequencing. CatB expression was markedly upregulated in ischemic brain myeloid cells, with higher levels in infiltrating macrophages than in microglia. Selective deletion of CatB in peripheral myeloid cells, but not in microglia, significantly reduced infarct size, mortality, and pro-inflammatory gene expression after tMCAO. Transcriptomic analyses showed suppression of inflammatory pathways and preservation of neuronal signaling in mice lacking macrophage-derived CatB. Cell type-resolved RNA sequencing revealed that CatB deficiency shifted infiltrating macrophages toward a pro-resolving, tissue-repair phenotype characterized by increased expression of M2-associated genes, including Chil3. Consistently, CatB-deficient macrophages displayed enhanced pro-resolving polarization in response to ischemic neuron-derived signals in vitro. CatB was also elevated in circulating Ly6C+ monocytes after stroke. These findings identify peripheral myeloid-derived CatB as a key driver of ischemic brain injury and a potential therapeutic target.
    Keywords:  cathepsin B; ischemic stroke; macrophage; microglia; neuroimmune cross‐talk
    DOI:  https://doi.org/10.1002/glia.70228
  14. Mol Neurobiol. 2026 Sep 26. pii: 930. [Epub ahead of print]63(1):
    West Nile Virus Exploits miR-155-5p-Mediated Regulation of TRIM32-IκBα Axis to Evade NF-κB-Mediated Innate Immune Responses in Human Microglial Cells.
    Vishal Keshri, Sunit K Singh.
      West Nile virus (WNV) is a neurotropic virus, having a single-stranded, positive-sense RNA genome belonging to the Flaviviridae family. WNV infection in the brain is associated with many neurological sequelae. Microglia are brain macrophages that respond to pathogenic breaches and eliminate threats. However, WNV is reported to evade cellular challenges and cause infection in the brain. In this study, we explored an underlying strategy by which WNV suppresses inflammation in microglial cells by increasing cellular microRNA-155-5p and dampening nuclear factor of kappa light-chain enhancer of activated B cells (NF-κB) signaling via tripartite motif-containing protein 32 (TRIM32). NF-κB is a crucial transcription factor involved in the production of pro-inflammatory cytokines and mediating cellular response. We observed increased expression of miR-155-5p in WNV-infected human microglial cells. The miR-155-5p-mediated regulation of TRIM32 and downstream NF-κB signaling was validated by miR-155-5p overexpression and knockdown in HMC3 cells. Increased miR-155-5p expression led to decreased TRIM32 expression. The decrease in TRIM32 sequestered the localization of inhibitor of nuclear factor of kappa light chain enhancer of activated B-cells, alpha (IκBα), and reduced its phosphorylation-mediated degradation. Consequently, resulting in decreased phosphorylation of NF-κB and decreased production of inflammatory cytokines. The protein expression patterns of TRIM32, p-IκBα, IκBα, p-NF-κB, NF-κB, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were assessed by immunoblotting. This study demonstrates that WNV modulates host cellular machinery by dysregulating miR-155-5p, thereby suppressing the host inflammatory response in human microglial cells.
    Keywords:  Central nervous system; Human microglia cells; IL-6; MicroRNA; NF-κB; TNF-α; TRIM32; West Nile virus
    DOI:  https://doi.org/10.1007/s12035-026-06233-9
  15. Mol Neurobiol. 2026 Sep 28. pii: 931. [Epub ahead of print]63(1):
    TREM2 Attenuates Microglial Pyroptosis in Sepsis-Associated Encephalopathy Through Modulation of the mtDNA-cGAS-STING Pathway.
    Peng Wang, Hanhong Zhuang, Jiemei Li, Xuemei Song, Siyi Wu, Yuanjie He, Jing He, Xian Qiu, Fei Lin.
      Microglial pyroptosis and the ensuing neuroinflammation are increasingly recognized as important contributors to sepsis-associated encephalopathy (SAE). Triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in sepsis-related neuroinflammation and SAE; however, how TREM2 is linked to microglial pyroptosis remains incompletely understood. This study aimed to investigate the potential involvement of the mtDNA-cGAS-STING pathway in TREM2-associated regulation of microglial pyroptosis in SAE. An SAE mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS), and an in vitro microglial pyroptosis model was generated in BV2 cells using LPS/nigericin. TREM2 knockout led to more severe neuronal damage and cognitive impairment in LPS-challenged mice. In vivo, TREM2 deficiency was associated with enhanced hippocampal microglial pyroptosis and inflammatory cytokine release, and TREM2 knockdown promoted pyroptosis and inflammatory responses in BV2 microglial cells in vitro. Mechanistically, our in vitro data suggest that TREM2 helps maintain mitochondrial homeostasis, reduces the accumulation of mitochondrial DNA (mtDNA) in the cytosol, and suppresses activation of the cGAS-STING pathway. Depletion of mtDNA with ethidium bromide (EtBr) partially reversed TREM2 knockdown-induced cGAS-STING overactivation, reduced pyroptosis and inflammatory cytokine release, and alleviated microglia-associated neuronal injury. Together, these findings suggest that TREM2 is associated with reduced microglial pyroptosis and microglia-associated neuronal injury in SAE, and that mtDNA-cGAS-STING signaling may participate in this process.
    Keywords:  Microglia; Pyroptosis; Sepsis-associated encephalopathy; TREM2; cGAS-STING
    DOI:  https://doi.org/10.1007/s12035-026-06230-y
  16. Cell Calcium. 2026 Sep 26. pii: S0143-4160(26)00091-6. [Epub ahead of print]138 103198
    Microglia calcium signals drive fine process retraction and promote susceptibility to status epilepticus.
    Chen Tan, Shuyan Dong, Xiaoyue Shi, Mu Zhang, Yu Liu, Peilong Cao, Guang-Hua Peng, Ji Xu.
      Microglia, the resident macrophages of the central nervous system, continuously survey the parenchyma with their highly motile processes. While calcium (Ca2+) signaling is a potential regulator of this process, the intrinsic mechanisms controlling process dynamics remain poorly defined. Here, we characterized microglial Ca2+ signals evoked by purinergic receptor activation both in vitro and in situ. In cultured microglia, UDP/UTP-induced P2Y6 receptor activation evoked robust Ca2+ signals with a sustained component mediated by store-operated Ca2+ entry (SOCE). In contrast, Ca2+ signals induced by P2Y6 and P2Y12/P2Y13 receptor activation in acutely isolated microglia or in situ microglia were dominated by intracellular store release, with minimal SOCE contribution. Functionally, Ca2+ signaling induced by P2Y6 activation or store depletion suppressed dorsal ruffling-an F-actin-dependent process-in cultured microglia. In brain slices, these Ca2+ signals triggered the retraction of fine processes and reduced process surveillance, while chemogenetic activation of Ca2+ signaling in vivo similarly decreased process complexity. Crucially, this microglial structural remodeling was associated with exacerbated status epilepticus. Thus, our study demonstrates that microglial Ca2+ signals act as a potent suppressor of process dynamics, thereby regulating neuronal excitability.
    Keywords:  Calcium signaling; Chemogenetics; Microglia; Status epilepticus; Store-operated calcium entry
    DOI:  https://doi.org/10.1016/j.ceca.2026.103198
  17. Biochem Biophys Res Commun. 2026 Sep 24. pii: S0006-291X(26)01394-X. [Epub ahead of print]838 154628
    Microglial FKBP51 drives immunometabolic dysfunction linking perioperative neurocognitive disorders and Alzheimer's disease.
    Shan Yang, Dan Wu, Yanjun Li, Yi Ding.
       BACKGROUND: Perioperative neurocognitive disorders (PND) and Alzheimer's disease (AD) are both important aging related cognitive disorders. Accumulating evidence suggests that they share common pathological mechanisms involving Aβ deposition, neuroinflammation, and immunometabolic imbalance. However, the key regulatory molecules linking these two conditions remain unclear. FKBP prolyl isomerase 51 (FKBP51) is an immune regulatory molecule widely involved in inflammation control and metabolic homeostasis maintenance, but its role in PND and AD is still unknown. This study aimed to investigate whether FKBP51 participates in the shared pathological processes of PND and AD by regulating microglial immunometabolism.
    METHODS: This study integrated transcriptomic data from PND and AD brain tissues to screen for commonly abnormally expressed metabolism related genes and analyzed key hub genes in relation to clinical cognitive scores. The Brain RNA-seq database, single cell RNA sequencing data, and immunofluorescence staining were used to determine the cellular localization and expression characteristics of FKBP51. Primary microglia were stimulated with oligomeric Aβ42, and Fkbp5 expression was knocked down using siRNA to evaluate its effects on microglial inflammatory responses and Aβ phagocytosis. Furthermore, single gene GSEA, Seahorse metabolic analysis, and ROS and JC-1 detection were combined to investigate the regulatory role of FKBP51 on microglial mitochondrial function and oxidative phosphorylation.
    RESULTS: Bioinformatics analysis identified FKBP51 as a key metabolism related hub gene that was commonly abnormally elevated in both PND and AD brain tissues, and its expression level was significantly correlated with cognitive decline in AD patients. Further studies revealed that FKBP51 was enriched in microglia and was significantly upregulated in brain tissues from AD patients and model mice. Aβ42 stimulation markedly induced FKBP51 expression in microglia. Functional experiments demonstrated that Fkbp5 knockdown enhanced microglial phagocytic capacity for Aβ and reduced the expression and secretion of proinflammatory factors. Mechanistic studies showed that FKBP51 was closely associated with pathways related to fatty acid oxidation and oxidative phosphorylation. Following FKBP51 inhibition, maximal respiration capacity and ATP production in microglia were significantly increased, mitochondrial membrane potential was improved, and ROS accumulation was markedly reduced. These metabolic improvements were accompanied by restoration of microglial phagocytic function and alleviation of the inflammatory state.
    CONCLUSIONS: This study reveals that FKBP51 is an important immunometabolic regulatory molecule linking the shared pathological processes of PND and AD. Abnormal upregulation of FKBP51 promotes microglial functional imbalance by inhibiting mitochondrial oxidative phosphorylation and inducing oxidative stress, thereby exacerbating Aβ related neuroinflammation and cognitive impairment. Targeting FKBP51 mediated microglial metabolic reprogramming may provide a novel intervention strategy for aging related cognitive disorders such as PND and AD.
    Keywords:  Alzheimer's disease; Bioinformatics; FKBP51; Immunometabolic; Microglia; Perioperative neurocognitive disorders
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154628
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒04 at 8:26.