bims-microg 2026-02-15 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–02–15
eighteen papers selected by
Marcus Karlstetter, Universität zu Köln

Systemic Inflammation Aggravates Retinal Ganglion Cell Vulnerability to Optic Nerve Trauma in Adult Rats.
Repetitive transcranial magnetic stimulation alleviates neuropathic pain via microglial polarization by modulating the METTL3/NMDAR2B/NLRP3 pathway.
Microglial histone H3K18 crotonylation promotes STAT1 expression and induces cognitive deficit in Alzheimer disease.
Downregulation of neuronal DRD2 drives microglia synaptic pruning and results in cognitive deficits by promoting CCL2 release in a rat model of chronic migraine.
TREM2 activation suppresses central sensitisation by promoting autophagy in a chronic migraine model with recurrent nitroglycerin stimulation in mice.
Mitochondrial DNA drives NLRP3-IL-1β axis activation in microglia by binding to NLRP3, leading to neurodegeneration in Parkinson's disease models.
MST1 promotes microglial pyroptosis and neuroinflammation in alzheimer's disease by regulating the novel DPP8/NLRP1/Caspase-1/GSDMD-N axis.
Microglia TFEB activation attenuates Alzheimer's disease pathology by enhancing autophagy-lysosomal function.
Capillary-Associated Microglia in Neurovascular Coupling: Localization, Mechanisms, and Disease Implications.
Inhibition of Sirpα expression enhances microglial phagocytic clearance of myelin debris and reduces neuronal PANoptosis after spinal cord injury.
TSC-associated microglial hyperactivity: enhanced calcium signaling, metabolism, and phagocytosis.
Mesoscale Recovery of Microglial and Neuronal Dynamics After Craniotomy Across Wide Cortex in Transgenic Mice.
Differential downstream signaling in microglia lacking Alzheimer's-related TREM2 or its adaptor TYROBP/DAP12.
PPARγ in microglia helps protect adolescent male mice from harmful effects of stress during early development.
Neutrophil-microglia interaction drives motor dysfunction in neuromyelitis optica model induced by subarachnoid AQP4-IgG.
Intranasal Human NSC-Derived EVs Therapy Can Restrain Inflammatory Microglial Transcriptome, and NLRP3 and cGAS-STING Signalling, in Aged Hippocampus.
Inhibition of TGF-β signaling in microglia stimulates hippocampal adult neurogenesis and reduces anxiety-like behavior in adult mice.
In Situ Redox-Omics Decoding of Nanoparticle-Protein Corona Interactions Drives the Mitochondrial Metabolic-Immunological Mechanism in Microglia.

Int J Mol Sci. 2026 Feb 03. pii: 1502. [Epub ahead of print]27(3):

Systemic Inflammation Aggravates Retinal Ganglion Cell Vulnerability to Optic Nerve Trauma in Adult Rats.

Giuseppe Rovere, Yolanda Caja-Matas, Beatriz Vidal-Villegas, José M Bernal-Garro, Paloma Sobrado-Calvo, Manuel Salinas-Navarro, Carlo Nucci, María Paz Villegas-Pérez, Manuel Vidal-Sanz, Marta Agudo-Barriuso, Francisco M Nadal-Nicolás.

  Systemic inflammation is increasingly recognized as a modifier of neurodegenerative outcomes in the central nervous system; however, its impact on retinal ganglion cell (RGC) survival and retinal microglial responses following optic nerve (ON) injury in vivo remains incompletely understood. In this study, we investigated how systemic lipopolysaccharide (LPS)-induced inflammation influences retinal microglial activation and RGC vulnerability under physiological conditions and after traumatic ON damage. In adult female rats, systemic LPS administration by intraperitoneal injection induced rapid and robust microglial activation, characterized by process retraction and soma hypertrophy within hours and promoting microglial proliferation at later stages but without causing RGC loss in intact retinas. Following ON crush, systemic inflammation did not affect early RGC degeneration but significantly exacerbated neuronal loss during the late acute phase. This increased vulnerability was accompanied by a marked rise in microglial density and a pronounced redistribution of microglia toward the central retina and the ON head, a region of heightened anatomical and metabolic susceptibility. Together, these findings demonstrate that, in rats, systemic inflammation alone is insufficient to induce RGC degeneration but acts as a potent priming factor that amplifies neurodegeneration in the context of axonal injury. The temporal and spatial specificity of microglial responses underscores their context-dependent role in retinal pathology and identifies systemic inflammatory status as a critical determinant of retinal outcome after trauma. Targeted, time-dependent modulation of microglial activation may therefore represent a promising therapeutic strategy for optic neuropathies.

Keywords:  adult albino female rat; inflammation; lipopolysaccharide; microglia activation; microglial cells; neuroinflammation; optic nerve crush; retina; systemic infection; traumatic injury

DOI:  https://doi.org/10.3390/ijms27031502
Front Immunol. 2025 ;16 1666920

Repetitive transcranial magnetic stimulation alleviates neuropathic pain via microglial polarization by modulating the METTL3/NMDAR2B/NLRP3 pathway.

Jiayi Zhu, Lei Li, Rongnan Shi, Fei Xing, Yue Yang, Zhangyu Xu, Qin Wang, Qi Deng, Dan Li, Maomao Huang, Jianxiong Wang.

   Introduction: Neuropathic pain (NeuP) remains a major clinical condition, and the existing interventions often fail to provide sufficiently satisfactory symptom control. Repetitive transcranial magnetic stimulation (rTMS) has gained attention as a potential non-invasive therapy for NeuP. However, the precise mechanisms underlying the effects of rTMS remain elusive.
Objective: This study explores the potential neurophysiological mechanisms of rTMS in NeuP, focusing on its modulation of the methyltransferase-like 3 (METTL3)/N-methyl-d-aspartate receptor subtype 2B (NMDAR2B)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) axis and microglial polarization.
Methods: CCI rats began to receive rTMS treatment once daily 7 days after the operation, and the treatment continued for 4 weeks. Pain and depression-like behaviors were evaluated by measuring the paw-withdrawal mechanical threshold (PWMT), thermal pain-induced paw-withdrawal latency (PWL), sciatic nerve function index (SFI), forced swimming test (FST) results, and new object preference index (NPI). The expression levels of relevant indicators were detected by immunofluorescence and western blot analyses, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA). BV2 microglia were cultured in Dulbecco's modified Eagle medium. After adding agonists and inhibitors of METTL3 and NMDAR2B, the microglia were treated with lipopolysaccharide (LPS; 100 µg/mL) for 12 h. The cells are divided into seven groups: Control (Con), LPS, LPS + magnetic stimulation (MS), LPS + METTL3 inhibition (sh-METTL3), LPS + METTL3 overexpression + magnetic stimulation (LPS+METTL3-OE+MS), LPS + NMDAR2B inhibition (sh-NMDAR2B), and LPS + NMDAR2B overexpression + magnetic stimulation (LPS+NMDAR2B-OE+MS). The expression levels of cell polarization markers, inflammatory factors, and related proteins were detected by methods such as immunofluorescence and western blot analyses, qRT-PCR, and ELISA.
Results: rTMS improved pain thresholds (PWMT, PWL, and SFI) and depressive-like behaviors, reduced immobility in the FST, and increased the NPI. It inhibited the levels of the pro-inflammatory markers interleukin (IL)-6, tumor necrosis factor (TNF)-α, NLRP3,TMEM119 and iNOS in the dorsolateral prefrontal cortex (DLPFC), while increasing the expression of IL-10 and Arg1. Moreover, rTMS decreased the expression levels of the M1-type marker CD86 of microglia and increased those of the M2-type marker CD206 and simultaneously decreased the expression of microglia activation marker Iba-1. rTMS simultaneously downregulated METTL3, N6-methyladenosine (m6A), NMDAR2B, and YTH domain-containing family 1 (YTHDF1). In the in vitro experiments, LPS-induced BV2 cells showed increased expression of CD86 increased (p < 0.01) as well as NLRP3, IL-6, TNF-α, and METTL3/m6A/YTHDF1/NMDAR2B (p < 0.01), and decreased expression of CD206 and IL-10. Magnetic stimulation reversed these effects, promoted the reduction of microglial marker Iba-1, increased M2 polarization and alleviated inflammation (p < 0.01). Inhibition of METTL3 or NMDAR2B alleviated LPS-induced inflammation. However, activation of METTL3 or NMDAR2B counteracted the effects of magnetic stimulation in improving inflammation (p < 0.01). In addition, suppressing or overexpressing METTL3, YTHDF1, and NMDAR2B correspondingly decreased or increased these effects, but modulation of NMDAR2B did not change the expression of METTL3/YTHDF1.
Conclusion: rTMS can affect the polarization state of microglia and neuroinflammation by regulating the METTL3/NMDAR2B/NLRP3 signaling pathway, thereby improving NeuP.

Keywords:  METTL3; NLRP3; NMDAR2B; microglial polarization; neuropathic pain; repetitive transcranial magnetic stimulation

DOI:  https://doi.org/10.3389/fimmu.2025.1666920
Front Immunol. 2026 ;17 1744375

Microglial histone H3K18 crotonylation promotes STAT1 expression and induces cognitive deficit in Alzheimer disease.

Ying Weng, Ting He, Mengzhu Li, Qiuzhi Zhou, Jiazhao Xie, Linyu Wei, Xin Wang, Jian-Zhi Wang, Maolin Zhong, Shihong Li.

   Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet the epigenetic mechanisms underlying its pathogenesis remain incompletely understood. Histone crotonylation, a novel post-translational modification, has been implicated in neuroinflammation. However, its role in AD-related cognitive impairment has not been elucidated.
Methods: Histone crotonylation was examined in 5xFAD and Aβ42-injected mice. Crotonic acid was administered intracerebroventricular (ICV) to elevate hippocampal histone crotonylation in wild-type mice. Cognitive function was assessed using behavioral tests. Synaptic integrity was evaluated via western blotting and Golgi staining. Microglial activation and co-localization of H3K18cr were determined by immunofluorescence. Transcriptomic analysis identified differentially expressed genes and enriched pathways. The role of signal transducer and activator of transcription 1 (STAT1) was validated in BV2 microglial cells using the STAT1 inhibitor fludarabine.
Results: Hippocampal pan-histone H3 crotonylation (H3Kcr) and H3K18cr were significantly upregulated in both 5xFAD and Aβ42-injected mice compared to controls. ICV injection of crotonic acid markedly elevated hippocampal H3Kcr and H3K18cr levels and induced significant cognitive deficits, shown by impaired novel object recognition and fear conditioning performance. Crotonic acid treatment resulted in synaptic dysfunction, including reduced synaptic markers (SYN1, SYT, GluA2, GluN2B) and decreased CA1 dendritic spine density. Crotonic acid also induced microgliosis with elevated Iba1 expression. H3K18cr was specifically upregulated in microglia, with no significant changes observed in neurons or astrocytes. Transcriptomic analysis identified 478 differentially expressed genes enriched predominantly in immune-related pathways, with STAT1 highlighted as a key upstream transcription factor. In BV2 cells, crotonic acid significantly increased total and phosphorylated STAT1 (Tyr701) levels via a JAK1-independent mechanism. Treatment with fludarabine effectively suppressed STAT1 expression and attenuated the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β.
Conclusion: This study provides the first evidence that elevated microglial H3K18cr contributes to AD-related cognitive impairment by promoting STAT1 expression and subsequent neuroinflammation. These findings identify microglial histone crotonylation as a novel epigenetic mechanism in AD pathogenesis and suggest that targeting the H3K18cr-STAT1 axis may represent a potential therapeutic strategy for AD.

Keywords:  STAT1; crotonic acid; histone crotonylation; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1744375
J Headache Pain. 2026 Feb 09. 27(1): 39

Downregulation of neuronal DRD2 drives microglia synaptic pruning and results in cognitive deficits by promoting CCL2 release in a rat model of chronic migraine.

Yaying Yang, Xiaojian Liu, Han Wang, Haifeng Wen, Juan Zhong, Wei Zhang, Yi Xian, Yonghu Wang, Guangcheng Qin, Dunke Zhang, Lixue Chen.

Chronic migraine (CM) is a disabling neurological condition increasingly recognized for its link to cognitive deficits and a potential higher dementia risk. Although microglia-mediated synaptic pruning has been associated with cognitive decline, its role in CM is not fully understood. The dopamine D2 receptor (DRD2), crucial for cognitive function, has been shown to affect synaptic pruning. This study investigates how DRD2 signaling influences microglial phagocytosis and synaptic integrity in CM. We established a chronic migraine model with repeated dural administration of inflammatory soup (IS), significantly reducing hippocampal DRD2, decreasing Postsynaptic density protein 95 (PSD95) levels, increasing microglial phagocytosis, and impairing spatial and non-spatial memory. These effects were lessened by administering the DRD2 agonist quinpirole. Transcriptomic analysis revealed that DRD2 deficiency causes overexpression of C-C motif chemokine ligand 2 (CCL2). Further mechanistic studies showed that DRD2 regulates microglial phagocytic activation through CCL2 and its receptor CCR2. This is the first identification of a "neuronal DRD2-CCL2-microglial phagocytosis-synaptic loss" axis, highlighting the active role of neuronal DRD2 in regulating synaptic pruning in CM. These findings suggest new treatment options for reducing cognitive impairment in CM by targeting the DRD2-CCL2-CCR2 pathway.

DOI: https://doi.org/10.1186/s10194-025-02229-3
Br J Pharmacol. 2026 Feb 11.

TREM2 activation suppresses central sensitisation by promoting autophagy in a chronic migraine model with recurrent nitroglycerin stimulation in mice.

Suifa Hu, Xiamin Liu, Lang Zhang, Sufang Zhong, Zhi Liang, Weixian Zeng, Li Yi, Zhiwen Zeng, Baodong Chen, Rikang Wang.

   BACKGROUND AND PURPOSE: Microglial activation plays a role in driving chronic migraine (CM). Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in brain microglia and impacts neuroinflammation in nervous system diseases. However, its role in CM is unclear. Here, we have investigated the role of microglial TREM2 in the development of CM.
EXPERIMENTAL APPROACH: We used male mice receiving repeated intraperitoneal nitroglycerin (NTG) injections as a CM model. Mechanical and thermal hypersensitivity were assessed by mechanical withdrawal threshold and thermal withdrawal latency. TREM2 knockout mice (TREM2-/-) and systemically administered TREM2 agonist COG1410 were evaluated for TREM2's role in CM. TREM2, calcitonin gene-related peptide (CGRP) and c-fos expression in the trigeminal nucleus caudalis (TNC) were measured for central sensitisation assessment. Immunohistochemical analyses and western blots measured protein expression in the TNC and BV-2 microglia. Quantitative real-time polymerase chain reaction (qRT-PCR) detected inflammatory factor expression.
KEY RESULTS: Recurrent NTG injection up-regulated TNC protein levels of TREM2, CGRP and c-fos. TREM2 loss accelerated NTG-induced CM development, increased CGRP and c-fos expression, and inhibited TNC autophagy. Conversely, COG1410 prevented hyperalgesia and reduced CGRP/c-fos expression in the TNC after recurrent NTG administration. In vitro, TREM2 knockdown enhanced the expression of inflammation-related genes and the mTOR/p70s6k pathway activation in lipopolysaccharide (LPS)-stimulated BV-2 microglia, whereas COG1410 significantly inhibited LPS-induced mTOR/p70s6k pathway activation and alleviated inflammatory responses.
CONCLUSION AND IMPLICATIONS: These data show that TREM2 plays a protective role in CM by modulating microglial activation and autophagy in the TNC via the mTOR/p70s6k pathway.

Keywords:  TREM2; chronic migraine; hyperalgesia; microglia; nitroglycerin; trigeminal nucleus caudalis

DOI:  https://doi.org/10.1111/bph.70353
Cell Death Dis. 2026 Feb 10.

Mitochondrial DNA drives NLRP3-IL-1β axis activation in microglia by binding to NLRP3, leading to neurodegeneration in Parkinson's disease models.

Qinglin Gan, Xiaolong Fu, Ting Zhou, Naiyu Fan, Nan Nan, Yi Wang, Yonggang Yang, Shiyi Gou, Lizhen Hu, Shaoyu Zhou.

Dysregulated mitochondrial DNA (mtDNA) promotes inflammatory response and disease progression. However, the mechanism and role of mtDNA-mediated inflammatory activation in the pathogenesis of Parkinson's disease (PD) are not yet clear. This study demonstrates that the injection of mtDNA into the substantia nigra pars compacta induces PD pathology in mice, characterized by the loss of dopaminergic (DA) neurons and the activation of microglia. Transcriptomic profiling of magnetic-activated cell sorting (MACS)-sorted cells reveals a pronounced upregulation of genes associated with the NLRP3 inflammasome pathway in microglia following the mtDNA administration. Critically, lipopolysaccharide (LPS) and rotenone induced in vivo and in vitro PD models show oxidized mtDNA (ox-mtDNA) release and microglial NLRP3-IL-1β axis activation as evidenced by upregulation of NLRP3 and IL-1β, caspase-1 cleavage, and IL-1β release. The role of mtDNA in activating the NLRP3-IL-1β axis is further validated in BV2 cells through exogeneous mtDNA transfection, while the NLRP3-IL-1β activation is negated in the LPS and rotenone induced model when mtDNA release is inhibited. Especially, oxidized mtDNA is superior to nonoxidized mtDNA in activating the NLRP3-IL-1β axis. NLRP3 knockdown in BV2 cells abolishes the activation of NLRP3-IL-1β axis induced by mtDNA or exposure of LPS and rotenone and mitigates the damage to SH-SY5Y cells in co-culture systems. Ox-mtDNA-mediated neuronal cell damage is initiated through binding to NLRP3, as demonstrated by co-immunoprecipitation and co-localization in BV2 cells. Molecular docking prediction and analysis of intrinsically disordered region (IDR) of NLRP3 indicate that ox-mtDNA interacts with the positively charged IDR of NLRP3. This interaction is validated by electrophoretic mobility shift and in vitro PYD-caspase-1 cleavage assays, demonstrating the formation of the ox-mtDNA-NLRP3 complex and subsequent activation of NLRP3. This study describes a critical role of mtDNA in activating microglial NLRP3-IL-1β axis, leading to neurodegeneration in PD pathology, which provides clear clues for developing anti-PD drugs targeting NLRP3.

DOI: https://doi.org/10.1038/s41419-026-08424-7
J Neuroinflammation. 2026 Feb 13.

MST1 promotes microglial pyroptosis and neuroinflammation in alzheimer's disease by regulating the novel DPP8/NLRP1/Caspase-1/GSDMD-N axis.

Dongqing Cui, Shuangwu Liu, Yanxia Liu, Shuqi Luo, Yurui Sheng, Shuaiyong Zhang, Pengfei Lin.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) induced disruption of brain homeostasis, leading to neuronal damage and cognitive impairment. Increasing evidence confirms that microglia-driven neuroinflammation serves as a core mechanism driving the progression of AD. Mammalian Ste20-like kinase 1 (MST1) plays a crucial regulatory role in apoptosis, immune inflammation, and oxidative stress. Our team's previous research revealed that MST1 regulates mitochondrial oxidative stress in neurons, contributing to the pathogenesis of AD. Here, we show that MST1 is activated as p-MST1 in the peripheral blood of AD patients, the serum of 5xFAD mice, and the hippocampal and cortical brain tissues of 5xFAD mice, an effect which was associated with microglial pyroptosis under chronic inflammatory stimulation. Knocking down MST1 in hippocampal and cortical tissues of 5xFAD mice improved cognitive deficits, reduced p-tau protein levels, and alleviated neurodegeneration and neuroinflammatory responses. Concurrently, MST1 knockdown suppressed abnormal microglial activation, decreased inflammatory cytokine release, and ultimately mitigated microglial pyroptosis. Mechanistically, we found that MST1 knockdown modulated DPP8 protein expression, thereby regulating the NLRP1/Caspase-1/GSDMD-N signaling axis to inhibit microglial pyroptosis and attenuate neuroimmune inflammation. In summary, MST1 knockdown improved AD disease progression by preventing disruption to the immune-inflammatory homeostasis of microglia. Therefore, we propose targeting MST1 as a promising therapeutic strategy to halt neuroinflammation and progression in Alzheimer's disease.

Keywords:  Alzheimer's disease; DPP8; MST1; Microglia; Neuroinflammation; Pyroptosis

DOI:  https://doi.org/10.1186/s12974-026-03732-3
J Neuroinflammation. 2026 Feb 11.

Microglia TFEB activation attenuates Alzheimer's disease pathology by enhancing autophagy-lysosomal function.

Yeji Kim, Tae-Young Ha, Oksana Kondaurova, Myung-Shik Lee, Keun-A Chang.

  Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, synaptic dysfunction, and cognitive decline. Impairment of microglial autophagy-lysosomal pathway (ALP) is increasingly recognized as a key driver of the disease progression. Transcription factor EB (TFEB), a master regulator of ALP, has emerged as a promising therapeutic target; however, its specific role in microglia remains unclear. Here, we aimed to determine the therapeutic effects of microglial TFEB expression in AD pathogenesis. We established a tamoxifen-inducible, microglia-specific TFEB-overexpressing 5xFAD mouse line (5xTFEB) and conducted behavioural testing, histopathology and biochemical analyses, live-cell imaging of Aβ phagocytosis, and bulk RNA sequencing. Differential gene expressions were analysed, and inflammasome activation was evaluated. Microglial TFEB overexpression restored ALP function, promoted phagolysosomal clearance of oligomeric Aβ, and reduced the amyloid burden in the cortex, hippocampus, and entorhinal cortex of the 5xFAD mice. These changes rescued memory deficits in both male and female 5xTFEB mice. Transcriptomic profiling revealed upregulation of ALP and downregulation of inflammatory signalling. Additionally, inflammasome activation was attenuated in 5xTFEB mice. Targeted TFEB activation in microglia reprograms degradative and immune pathways, enhancing Aβ clearance while alleviating neuroinflammation and cognitive impairment in AD. Overall, microglial TFEB modulation is a promising cell-type-specific therapeutic strategy for AD and related neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Amyloid beta; Autophagy-lysosomal pathway; Microglia; Neuroinflammation; TFEB

DOI:  https://doi.org/10.1186/s12974-026-03728-z
J Neuroinflammation. 2026 Feb 11.

Capillary-Associated Microglia in Neurovascular Coupling: Localization, Mechanisms, and Disease Implications.

Haofan Lu, Yonggang Zhang, Cheng Chen, Hairou Xie, Yuntao Li, Sheng Qiu.



Keywords:  Blood-brain barrier; Capillaries; Capillary-Associated microglia; Neurovascular coupling; Neurovascular unit; P2Y12R

DOI:  https://doi.org/10.1186/s12974-026-03723-4
Int J Surg. 2026 Feb 12.

Inhibition of Sirpα expression enhances microglial phagocytic clearance of myelin debris and reduces neuronal PANoptosis after spinal cord injury.

Wu Jiang, Dejia Kong, Junsheng Lou, Maoqiang Li, Mengran Jin, Liulong Zhu, Yihe Hu, Junsong Wu.

   BACKGROUND: Spinal cord injury (SCI) is a devastating neurological disorder that leads to significant morbidity and mortality. Myelin debris clearance is a crucial step in the recovery process after SCI. Microglial phagocytosis plays a vital role in this process, but the underlying regulatory mechanisms are still poorly understood. This study investigates the role of signal regulatory protein alpha (Sirpα) in myelin debris clearance and neuronal survival after SCI.
METHOD: Gene Set Enrichment Analysis (GSEA) to analyze genes that inhibit microglial phagocytosis in the GSE196928 dataset. Using siRNA-mediated Sirpα knockdown, we observed a significant increase in phagocytic uptake of myelin debris, as quantified by flow cytometry, immunofluorescence, and Enzyme-linked immunosorbent assay. Moreover, inhibition of Sirpα expression by siRNA promotes debris clearance and reduces PANoptosis of neurons after SCI, as shown by Western Blot and immunofluorescence.
RESULTS: Sirpα is the core gene that negatively regulates the phagocytosis of microglia after SCI. Myelin debris induces the occurrence of PANoptosis in neurons. Mechanistically, inhibition of Sirpα expression enhanced the phagocytosis of myelin debris through the activation of Spleen Tyrosine Kinase (Syk)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Pharmacological inhibition of PI3K or Syk reversed the pro-phagocytic effects in Sirpα-knockdown microglia. In addition, overexpression of NOD-like receptors family pyrin domain containing 12 (NLRP12) reversed the reduction of neuronal PANoptosis in co-cultured Sirpα-knockdown microglia.
CONCLUSIONS: We have demonstrated that inhibition of Sirpα expression enhances myelin debris clearance by microglia through the activation of the Syk/PI3K/Akt pathway and suppresses NLRP12-mediated PANoptosis of neurons, effectively reducing neuronal death and promoting neurological recovery after SCI. Our findings provide novel insights into the therapeutic potential of targeting Sirpα for SCI treatment.

Keywords:  PANoptosis; Sirpα; microglia; myelin debris; spinal cord injury

DOI:  https://doi.org/10.1097/JS9.0000000000004109
Acta Neuropathol. 2026 Feb 13. 151(1): 16

TSC-associated microglial hyperactivity: enhanced calcium signaling, metabolism, and phagocytosis.

Rozemarijn S Kalf, Mark J Luinenburg, Giulia Dematteis, Mirte Scheper, Jasper J Anink, Giulia Cavallo, Andrea Mattarei, Wim Van Hecke, Angelika Mühlebner, Laura Tapella, James D Mills, Dmitry Lim, Eleonora Aronica.

  Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with prominent neurological manifestations, most notably epilepsy, and is frequently accompanied by a wide range of neuropsychiatric comorbidities. Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway plays a central role in TSC pathology, disrupting both general brain development and specific molecular processes such as metabolism. While much attention has focused on neurons and astrocytes in these TSC-related alterations, the contribution of microglia remains relatively underexplored. In this study, we first analysed the transcriptomic profiles from resected TSC brain tissue and identified evidence of calcium (Ca2+) dysregulation in TSC microglia. In order to investigate the functional consequences, we then examined induced pluripotent stem cell (iPSC) derived microglia-like (iMGL) cells from TSC patients. Our findings reveal that these iMGL cells displayed markedly altered Ca2⁺ signalling, characterized by impaired store-operated calcium entry (SOCE) and an increase in mitochondrial Ca2⁺ uptake. These changes are accompanied by elevated mitochondrial respiratory activity, suggesting a shift in metabolic state. In addition, TSC iMGL cells displayed increased phagocytic activity and an altered inflammatory responsiveness, consistent with a dysregulated microglial activation state. Supporting these functional alterations in iMGL cells, transcriptomic analysis of TSC brain tissue revealed upregulation of several genes associated with lipid metabolism, phagocytosis, and innate immune activation, with partial overlap with stage 2 disease-associated microglia (DAM)-like programs. Together these findings suggest that microglial dysfunction may represent a relevant component of TSC pathophysiology.

Keywords:  Calcium signalling; Epilepsy; Microglia; Phagocytosis; Tuberous sclerosis complex

DOI:  https://doi.org/10.1007/s00401-026-02986-8
Adv Sci (Weinh). 2026 Feb 11. e12192

Mesoscale Recovery of Microglial and Neuronal Dynamics After Craniotomy Across Wide Cortex in Transgenic Mice.

Guihua Xiao, Zhilei Wang, Pengchang Zheng, Jingyu Xie, Yangzhen Wang, Yun Chen, Zilin Wang, Ao Li, Minghuan Wang, Quanbo Ji, Can Gao, Di Yao, Lingbo Li, Jiangbei Cao.

  Craniotomy is commonly used to access the brain for neurosurgical procedures or neural probe implantation. However, the dynamic structural and functional changes in microglia and neurons during postoperative recovery remain poorly understood. Here, we utilize mesoscale fluorescence imaging and multiple transgenic mouse models (Cx3cr1-GFP, Thy1-YFP, and Rasgrf2-2A-dCre/Ai148D) to longitudinally record the dynamic recovery of microglia and neurons across the wide cortex over 50 days after craniotomy. Our findings reveal that both neuronal and microglial structures and functions are significantly altered after surgery, yet their recovery to the first day after craniotomy follow distinct temporal patterns. Microglia exhibit the most rapid structural changes, reaching peak inflammatory response within approximately 10 days. Subsequently, neuronal structural fluorescence intensity peaks around 14 days post-surgery, showing a strong positive correlation with microglial changes. Finally, neuronal functional dynamics are assessed using drifting grating visual stimulation, with functional modularity indices to quantify network integrity. We observe that functional modularity undergoes significant disruption, reaching its peak disruption at approximately 21 days post-surgery. These findings provide new insights into the dynamic process following craniotomy and offer a novel perspective on neuroimmune interactions in traumatic conditions.

Keywords:  craniotomy; dynamics; mesoscale; microglia; neurons

DOI:  https://doi.org/10.1002/advs.202512192
Mol Neurodegener Adv. 2026 ;2(1): 8

Differential downstream signaling in microglia lacking Alzheimer's-related TREM2 or its adaptor TYROBP/DAP12.

Gabriela E Farias Quipildor, Ramona Belfiore, Khaled Althobaiti, Zahra Najarzadeh, Charles Glabe, Benjamin P Readhead, Sam Gandy, Stephen R J Salton, Michelle E Ehrlich.

  Microglia, the primary immune cell in the brain, have multiple activation phenotypes involved in broad functions within the brain, playing roles in neurotoxicity/neuroprotection, release of inflammatory and anti-inflammatory cytokines, and in cell survival, proliferation, and phagocytosis. TREM2 and TYROBP form a transmembrane complex in microglia that modulates intracellular signaling networks, and these proteins are essential regulators of the transition from homeostatic to activated microglia. Recent findings support a TREM2-independent molecular signature that is involved in the early transition of homeostatic to disease-associated microglia (DAM), with the next sequential step of DAM activation from stage 1 to stage 2 being TREM2-dependent. However, the underlying mechanisms determining how TREM2 or TYROBP regulate these downstream phenotypes are largely unknown. We isolated primary microglia from C57BL/6 wild-type (WT) controls, Trem2 knock-out (KO), and Tyrobp KO mice at post-natal day 0-3. Cells were treated with Alzheimer's disease (AD)-relevant stimuli, such as amyloid beta (Aβ) oligomers or fibrils, or 'neuroinflammatory-like' stimuli, such as lipopolysaccharide (LPS). We explored protein and gene expression in the presence or absence of inhibitors of the TREM2/TYROBP downstream signaling pathway. We also performed a high-throughput Olink proteomic analysis of conditioned media from WT, Trem2 KO, and Tyrobp KO stimulated with either LPS or Aβ oligomers or fibrils. Our results show that the absence of either TREM2 or TYROBP is associated with increased basal levels of phosphorylated ERK in primary microglia compared to WT controls. In addition, Trem2 KO and Tyrobp KO cells show a less ramified cell morphology at baseline, as compared to WT microglia. Moreover, stimulating primary microglia with either Aβ oligomers or LPS leads to differential protein and gene expression in cells lacking TREM2 or TYROBP. The dysregulated downstream signal transduction and morphology in the absence of TREM2 or TYROBP suggest their essential roles not only in microglial homeostasis but also in their activation in response to different stimuli.
Graphical abstract:
Supplementary Information: The online version contains supplementary material available at 10.1186/s44477-025-00012-x.

Keywords:  DAP12; Microglia; Signal transduction; TREM2; TYROBP

DOI:  https://doi.org/10.1186/s44477-025-00012-x
Brain Behav Immun. 2026 Feb 09. pii: S0889-1591(26)00231-X. [Epub ahead of print] 106483

PPARγ in microglia helps protect adolescent male mice from harmful effects of stress during early development.

Zhe Liu, Jiutai Wang, Yan Ge, Yu Wang, Hanyi Ling, Yan Liu, Jinqiang Zhang, Zili You, Yue Han.

  Deficiency in the expression or activity of the nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) has been observed in autism spectrum disorder, bipolar disorder and Alzheimer's disease. Here we showed that separating mouse pups from their mothers for three hours daily during the first two weeks of life downregulated PPARγ, leading to pro-inflammatory polarization and activation of microglia in the hippocampus, which results in more severe responses to subsequent chronic restraint stress in adolescent animals. These effects of maternal separation were reversed by activating PPARγ with pioglitazone at 30 mg/kg/day for one week, which also stimulated hippocampal neurogenesis. Knocking out PPARγ specifically in microglia reduced neural activity and dendritic spine density in the cortex and hippocampus and led to depressive-like behaviors in mice. These results suggest that PPARγ expression enables microglia to "remember" previous exposure to stress and thereby influence responses to future stress. The findings may help guide interventions against stress and related psychological disorders.

Keywords:  Early life stress; Electrophysiology; Microglia; PPARγ; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.bbi.2026.106483
J Clin Invest. 2026 Feb 10. pii: e199706. [Epub ahead of print]

Neutrophil-microglia interaction drives motor dysfunction in neuromyelitis optica model induced by subarachnoid AQP4-IgG.

Fangfang Qi, Vanda A Lennon, Shunyi Zhao, Yong Guo, Husheng Ding, Caiyun Liu, Whitney M Bartley, Tingjun Chen, Claudia F Lucchinetti, Long-Jun Wu.

  Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 water (AQP4) channels. Yet, the mechanisms underlying neutrophil recruitment and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating mouse monoclonal AQP4-IgG. Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment, but no blood-brain barrier leakage. Motor impairment and neuronal dysfunction both reversed when AQP4-IgG infusion stopped. Two-photon microscopy and electron-microscopy-based reconstructions revealed physical interaction of infiltrating neutrophils with microglia. Ablation of either peripheral neutrophils or microglia attenuated the motor deficit, highlighting their synergistic pathogenic roles. Of note, mice lacking complement receptor C5aR1 exhibited reduction in neutrophil infiltration, microglial lysosomal activation, neuronal lipid-droplet burden and motor impairment. Pharmacological inhibition of C5aR1 recapitulated this protection. Immunohistochemical analysis of an NMO patient's spinal cord revealed disease-associated microglia surrounding motor neurons in non-destructive lesions. Our study identifies neutrophil-derived C5a signaling through microglial C5aR1 as a key early driver of reversible motor neuron dysfunction in the precytolytic phase of NMO.

Keywords:  Autoimmune diseases; Autoimmunity; Neuroscience

DOI:  https://doi.org/10.1172/JCI199706
J Extracell Vesicles. 2026 Feb;15(2): e70232

Intranasal Human NSC-Derived EVs Therapy Can Restrain Inflammatory Microglial Transcriptome, and NLRP3 and cGAS-STING Signalling, in Aged Hippocampus.

Leelavathi N Madhu, Maheedhar Kodali, Shama Rao, Sahithi Attaluri, Raghavendra Upadhya, Goutham Shankar, Bing Shuai, Yogish Somayaji, Shruthi V Ganesh, Vignesh S Kumar, Jeswin E James, Padmashri A Shetty, Avery LeMaire, Xiaolan Rao, James J Cai, Ashok K Shetty.

  Neuroinflammaging, a moderate, chronic, and sterile inflammation in the hippocampus, contributes to age-related cognitive decline. Neuroinflammaging comprises the activation of the nucleotide-binding domain, leucine-rich repeat family, and pyrin domain-containing 3 (NLRP3) inflammasomes, and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway that triggers type 1 interferon (IFN-1) signalling. Studies have shown that extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSC-EVs) contain therapeutic miRNAs that can alleviate neuroinflammation. Therefore, this study examined the effects of late middle-aged (18-month-old) male and female C57BL6/J mice receiving two intranasal doses of hiPSC-NSC-EVs on neuroinflammaging in the hippocampus at 20.5 months of age. Compared with animals receiving vehicle treatment, the hippocampus of animals receiving hiPSC-NSC-EVs exhibited reductions in astrocyte hypertrophy, microglial clusters, and oxidative stress, along with elevated expression of antioxidant proteins and genes that maintain mitochondrial respiratory chain integrity. Moreover, hiPSC-NSC-EVs therapy decreased the levels of various proteins involved in the activation of the NLRP3 inflammasome, p38/mitogen-activated protein kinase, cGAS-STING-IFN-1, and Janus kinase and signal transducer and activator of transcription signalling pathways. Furthermore, in vitro assays using genetically engineered RAW cells and hiPSC-NSC-EVs, with or without targeted depletion of specific miRNAs, demonstrated that miRNA-30e-3p and miRNA-181a-5p, both present in hiPSC-NSC-EVs, can significantly inhibit the activation of the NLRP3 inflammasome and the STING pathway, respectively. Additionally, single-cell RNA sequencing conducted 7 days post-treatment revealed that hiPSC-NSC-EVs induce widespread transcriptomic changes in microglia, including increased expression of numerous genes that enhance oxidative phosphorylation and reduced expression of abundant genes that drive multiple proinflammatory signalling pathways. These changes mediated by hiPSC-NSC-EVs were also associated with improved cognitive and memory function. Thus, intranasal hiPSC-NSC-EVs therapy in late middle age can effectively diminish proinflammatory microglial transcriptome and signalling cascades that drive neuroinflammaging in the hippocampus, contributing to better brain function in old age.

Keywords:  GeneWalk; brain aging; hippocampus; inflammasomes; interferon‐1 signalling; microglia; mitochondrial function; mitogen‐activated protein kinase signalling; neuroinflammation; scRNA‐seq

DOI:  https://doi.org/10.1002/jev2.70232
Nat Commun. 2026 Feb 09. 17(1): 1440

Inhibition of TGF-β signaling in microglia stimulates hippocampal adult neurogenesis and reduces anxiety-like behavior in adult mice.

Kierra Ware, Joshua Peter, Jake Yazell, Christina Thapa, Aleksandr Taranov, Alicia Bedolla, Claire Distel, Sven Lammich, Regina Feederle, Alice Sülzen, Shane Liddelow, Krishna Roskin, Yu Luo.

Adult neurogenesis in the subgranular zone (SGZ) has been implicated in cognitive and affective functions. The role of neuroinflammation and reactive microglia in SGZ neurogenesis is not well understood. TGF-β signaling is critical to maintaining microglia homeostasis in the adult brain. To investigate the role of microglia in SGZ neurogenesis, using microglia-specific inducible knockout (iKO) mice for TGF-β1 ligand or receptor (Alk5 or Tgfbr2), here we show that TGF-β-deficient microglia increase adult neurogenesis in the SGZ, accompanied by altered anxiety-like behavior in KO mice. Single-cell RNAseq (ScRNAseq) analysis shows decreased PTEN signaling, and immunohistochemistry shows increased mTOR activity in DCX+ newly born neuroblasts at the SGZ in iKO mice. Inhibition of mTOR signaling by rapamycin reverses the heightened SGZ neurogenesis in iKO mice. This study reveals the role of microglia in regulating hippocampal adult neurogenesis via the PTEN-mTOR pathway and its potential implications for behavioral and affective functions.

DOI: https://doi.org/10.1038/s41467-026-68885-4
ACS Nano. 2026 Feb 09.

In Situ Redox-Omics Decoding of Nanoparticle-Protein Corona Interactions Drives the Mitochondrial Metabolic-Immunological Mechanism in Microglia.

Ze-Kun Chen, Ming Yu, Zhong-Yao Li, Ling-Li Zheng, Ji-Chao Zhang, Ting-Ting Liu, Zhuo Yang, Ling Li, Zhi-Yuan Lu, Tian-Tian Wei, Hua Wang, Bo Han, Wei Yu, Peng-Fei Tu, Ke-Wu Zeng.

  Nanoparticle-protein corona interactions critically determine biological responses but remain poorly characterized in living systems due to the lack of noninvasive analytical tools. In this study, we developed a redox-omics strategy that facilitated the in situ mapping of corona composition by tracking cysteine thiol oxidation markers induced by nanoparticles. As a research tool, we synthesized natural-organic-matter-derived carbon dots (nCDs) with dual superoxide dismutase/catalase-mimetic activity. A global redox-omics analysis identified 104 proteins that demonstrated significant redox reactions in response to treatment with nCDs. In particular, we found that nCDs specifically induced a conformational change in isocitrate dehydrogenase 1 (IDH1) by selectively reversing the oxidation of cysteine 269 (Cys269). In the mechanism, the site-specific reduction in cysteine 269 (Cys269) triggered a conformational switch of IDH1 that restored mitochondrial α-ketoglutarate flux and NADPH homeostasis, thereby blocking cytosolic mitochondrial DNA (mtDNA) leakage and subsequent cGAS-STING-driven neuroinflammation. Crucially, the nCDs-mediated metabolic checkpoint control inhibited the pro-inflammatory (M1) phenotypes of microglia, thereby achieving therapeutic efficacy in both zebrafish and murine ischemic stroke models, without inducing detectable toxicity. Collectively, we developed a label-free platform enabling in situ decoding of protein corona interactions via redox-sensitive cysteine profiling, eliminating the need for nanoparticle surface modifications.

Keywords:  carbon dots; conformational change; cysteine thiol; microglial polarization; protein corona interactions; redox-omics

DOI:  https://doi.org/10.1021/acsnano.5c21740