bims-microg 2026-08-23 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–08–23
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

NF1 Leucine Rich Domain-Derived Extracellular Vesicles Remodel the Glioblastoma Immune Microenvironment via an ADAM17-Associated Inflammatory Program.
Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence.
TAB2 Causes Neuronal Damage by Aggravating Microglia-Mediated Neuroinflammation in Parkinson's Disease.
Extracellular CIRP Dysregulates Microglial Efferocytosis in Acute Ischemic Stroke via the TLR4/miR-155/MafB Axis.
Microglial Deubiquitinase OTUD7B Stabilizes STAT3 to Promote Neuroinflammation and Cognitive Decline in Alzheimer's Disease.
Nano Proton Scavengers Modulate Endosomal pH to Inhibit Microglial Activation and Enhance Stroke Recovery.
Convection-enhanced delivery of dexamethasone in glioma models suppresses myeloid inflammation while avoiding systemic toxicities.
HMGB1 aggravates neuronal ferroptosis and microglial inflammation in metabolic syndrome-associated cognitive impairment via the NRF2-autophagic flux axis.
Maternal sleep deprivation reshapes offspring hippocampal development through a Trem2-centered microglial program revealed by single-nucleus and spatial transcriptomics.
A human pluripotent stem cell triculture platform to elucidate microglial regulation of retinal ganglion cells in neuroinflammation.
β-Endorphin contributes to psychological stress- associated hippocampal microglial alterations and cognitive impairment.
Circadian rhythms in microglia mediate early life synaptic development in a sex-specific manner.
BDKRB2 upregulation by dystrophic microglia drives pain hypersensitivity in aged mice.
Spatial transcriptomics revealed the regulatory role of CCN1 to microglia distribution through region-specific cellular interactions.
Adenosine 2A receptor drives microglial efferocytosis to accelerate white matter repair and functional recovery after stroke.
Gut-derived small extracellular vesicles support trained innate immune tolerance in murine microglial cells.
Development and validation of a long-term co-maturation protocol for human stem cell-derived microglia and neuronal networks.
Loss of PHD3 rescues mice from Neuroinflammation and cognitive disorders induced by lipopolysaccharide or surgical trauma.
Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses Under Amyloid Stress.
KDM4A promotes microglial pyroptosis and neuropathic pain via the MEG3/SMURF2/HES1 axis.

J Extracell Vesicles. 2026 Aug;15(8): e70355

NF1 Leucine Rich Domain-Derived Extracellular Vesicles Remodel the Glioblastoma Immune Microenvironment via an ADAM17-Associated Inflammatory Program.

Yuganthini Vijayanathan, Jacqueline Yt Yeo, Janice Hy Tan, Fikri Bin Mohamed, Bernett Lee, Tatsuya Kozaki, Nurashikin Abdul Halim, Rachel Ly Ho, Hai Tao Tu, Zhi Wei Zhang, Jann N Sarkaria, Li Zeng, Florent Ginhoux, Ivy Aw Ho.

  Extracellular vesicles (EVs) are increasingly recognized as mediators of intercellular communication in cancer. We previously demonstrated that re-expression of the leucine-rich domain (LRD) of neurofibromin (NF1) suppresses glioblastoma (GBM) invasion and limits microglia/macrophage infiltration into the tumor microenvironment (TME). Given the central role of tumor-associated microglia/macrophages (TAMs) in GBM progression, we investigated whether NF1-LRD-containing EVs (NF1-LRD-EVs) could modulate TAM function and remodel the TME. Our results showed that NF1-LRD-EVs attenuated microglia and macrophage recruitment in migration assays, consistent with reduced microglia/macrophage recruitment observed in vivo. In parallel, treatment with NF1-LRD-EVs enhanced phagocytic activity of both microglia and iPSC-derived macrophages, accompanied by induction of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and downregulation of immunosuppressive mediators such as Arginase-1 and IL-10. Mechanistically, NF1-LRD-EVs induced ADAM17-associated inflammatory signaling, accompanied by NF-κB activation. Pharmacological inhibition of ADAM17 reduced TNF-α release and attenuated NF-κB activation, supporting a role for ADAM17-dependent signaling in amplifying this inflammatory response. Together, these findings show that NF1-LRD-EVs reprogram TAMs toward a pro-inflammatory phenotype and modulate the GBM immune microenvironment. These results provide a framework for understanding NF1-LRD-EV-mediated immune regulation and support further investigation of EV-mediated immune modulation of the TME.

Keywords:  ADAM17; NF1; TNF‐α; extracellular vesicles; glioblastoma; macrophage; microglia

DOI:  https://doi.org/10.1002/jev2.70355
Nat Neurosci. 2026 Aug 17.

Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence.

Xin Yan, Christina Georgopoulou, Hang-Mao Lee, Ala Ahrari, Jenny Russ, Vijay Chandrasekar, Tim Ducksch, Giuliano Crispatzu, Valentina Talevi, Liang Qiao, Shobhit Agrawal, Sophie Crux, Andrew W Daman, Lena Wischhof, Miriam Stork, Margit Zweyer, Emma Dorotea Zanfi, Manon Chevallot-Beroux, Yunxiao Li, Elena De-Domenico, Dina Hüsson, Lorenzo Bonaguro, Yuanfang Li, Jonas Schulte-Schrepping, Qingyi Liang, Ketty Kessler, Dan Ehninger, Shahin Rafii, Jiankai Luo, Andreas Hermann, Annett Halle, Ying Liu, Elvira Mass, Melania Capasso, Hiroki Kato, Joachim L Schultze, Pierluigi Nicotera, Daniele Bano, Steven Zvi Josefowicz, Martin Fuhrmann, Thomas Ulas, Marc Beyer, Juntang Lin, Monique M B Breteler, N Ahmad Aziz, Paolo Salomoni.

Aging-associated loss of chromatin compaction is linked to derepression of retrotransposable elements (RTEs) in mouse and human tissues. Whether such RTE transcription contributes to the microglia activation that is common in aged brains is unknown. Here, we show that DAXX, a histone chaperone and RTE repressor, is downregulated during aging, preserves microglia homeostasis and inhibits cellular senescence. Loss of Daxx in young-adult microglia drives a reactive phenotype marked by chromatin decompaction at RTEs, loss of homeostatic markers, cell cycle re-entry and behavioral changes. This state leads to DNA damage and microglial depletion, followed by replacement with DAXX-deficient/Apoehigh microglia displaying features of senescence. Sustained induction of senescence relies on promyelocytic leukemia protein, a DAXX-interacting factor and interferon target. Together, these findings highlight the importance of heterochromatin maintenance in preserving adult microglial identity and plasticity, with broader implications for brain homeostasis, healthy aging and behavior.

DOI: https://doi.org/10.1038/s41593-026-02404-y
Adv Sci (Weinh). 2026 Aug 17. e77175

TAB2 Causes Neuronal Damage by Aggravating Microglia-Mediated Neuroinflammation in Parkinson's Disease.

Yanhao Zhao, Zimeng Huang, Jianing Gao, Aolan Li, Huizhi Wang, Yingchuan Chen, Guanyu Zhu, Xin Zhang, Yin Jiang, Moxuan Zhang, Fangang Meng, Jianguo Zhang, Tingting Du.

  Neuroinflammation plays a key role in exacerbating dopaminergic neuron loss in Parkinson's disease (PD). We identified TAB2 as an early-stage biomarker, which was elevated in PD patients' microglia. However, the role of TAB2 in the pathogenesis of PD remains unknown. In this study, we found that Tab2 knockdown inhibited the activation of microglia and protected neurons in PD models. STAT3, as a transcription factor for TAB2, regulated TAB2 expression. Mechanistically, TAB2 interacted with α-synuclein and facilitated the recognition of K63-linked ubiquitin chains, leading to the formation of the TAK1-TABs complex and activation of TAK1, which was ultimately followed by activation of the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, microglia-specific knockdown of Tab2 significantly inhibited microglia activation, protected dopaminergic neurons, improved motor function, and attenuated anxiety-like behaviors in PD mouse model. We further showed that the FDA-approved drug, lumacaftor, suppressed microglial TAB2 expression and had potent anti-inflammatory and neuroprotective effects in PD models. Taken together, our study reveals that the STAT3-TAB2-NF-κB-IL-1β positive feedback axis in microglia is a crucial checkpoint that exacerbates neuroinflammation in PD. Therefore, these findings identify a pivotal role of TAB2 in regulating microglia-mediated neuroinflammation, suggesting that targeting TAB2 may be a possible therapeutic strategy for PD.

Keywords:  TAB2; lumacaftor; neuroinflammation; parkinson's disease

DOI:  https://doi.org/10.1002/advs.77175
Adv Sci (Weinh). 2026 Aug 15. e77053

Extracellular CIRP Dysregulates Microglial Efferocytosis in Acute Ischemic Stroke via the TLR4/miR-155/MafB Axis.

Dmitriy Lapin, Dilara Aylar, Archna Sharma, Ping Wang.

  Efferocytosis, the phagocytic clearance of dying cells, by microglia is crucial for limiting neuroinflammation and promoting resolution in ischemic stroke. Extracellular cold-inducible RNA-binding protein (eCIRP) is an inflammatory mediator that impairs macrophage bacterial phagocytosis in sepsis and radiation injury, but its role in microglial efferocytosis in ischemic stroke has not yet been studied. Using a transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke, this study demonstrated that eCIRP is released into the cerebrospinal fluid and microglial expression of the crucial efferocytic receptor MerTK decreases in tMCAO mice. CIRP deficiency significantly improved MerTK expression and microglial efferocytosis in tMCAO mice, reducing brain infarction, inflammation, neurological deficit, and survival in acute stroke. eCIRP induces pro-inflammatory micro-RNA 155 (miR-155) via TLR4, which suppresses its target pro-efferocytic transcription factor MAF bZIP (MafB), downregulating MerTK and the downstream cytoskeletal regulators, to impair microglial efferocytosis. Pharmacological blockade of eCIRP-TLR4 interaction using small peptide C23 attenuates miR-155 induction, restores MerTK expression, rescues microglial efferocytosis, and improves outcomes in tMCAO mice. This study uncovers a previously unknown pathway through which eCIRP signaling impairs neuroprotective efferocytic microglial function in ischemic stroke, suggesting that targeting eCIRP may promote functional recovery after stroke.

Keywords:  C23; TLR4/miR‐155/MafB axis; eCIRP; efferocytosis; ischemic stroke; microglia; neuroinflammation

DOI:  https://doi.org/10.1002/advs.77053
Adv Sci (Weinh). 2026 Aug 19. e23043

Microglial Deubiquitinase OTUD7B Stabilizes STAT3 to Promote Neuroinflammation and Cognitive Decline in Alzheimer's Disease.

Luyao Li, Hao Tang, Qin Yu, Yuyang Zhang, Binglu Shi, Ying Kong, Leiyu Xu, Jingjing Shao, Chenghong Hu, Lingyu She, Zhe Wang, Haiyi Chen, Aleksandr V Samorodov, Gang Cao, Xia Zhao, Yi Wang.

  Neuroinflammation driven by microglial activation is a defining feature of Alzheimer's disease (AD), yet the molecular mechanisms sustaining this proinflammatory state remain unclear. Here, we identify the deubiquitinase OTUD7B as a critical regulator of microglial activation and AD pathology. OTUD7B expression was markedly elevated in microglia from AD mouse models and human patient datasets. Genetic ablation of OTUD7B markedly attenuated microglial activation and cytokine release, alleviated neuronal injury, and improved cognitive performance in AD mice. Mechanistically, OTUD7B directly interacted with STAT3 and removed K48-linked ubiquitin chains at lysine 283, thereby stabilizing STAT3, promoting its nuclear translocation, and enhancing transcription of proinflammatory mediators. Integrative transcriptomic analysis revealed that OTUD7B deficiency suppressed proinflammatory transcriptional programs in microglia. Together, these findings uncover an OTUD7B-STAT3 signaling axis that sustains microglial-driven neuroinflammation and identify OTUD7B as a potential therapeutic target for mitigating neurodegenerative pathology in AD.

Keywords:  OTUD7B; STAT3; alzheimer's disease; deubiquitinating enzymes; microglial; neuroinflammation

DOI:  https://doi.org/10.1002/advs.202523043
Adv Sci (Weinh). 2026 Aug 21. e77311

Nano Proton Scavengers Modulate Endosomal pH to Inhibit Microglial Activation and Enhance Stroke Recovery.

Xuanlin Wang, Yujing Shi, Zehua Gao, Jing Wang, Changsheng Liu.

  Endosomes play a crucial role in immune regulation, yet their effect on microglial behavior in ischemic stroke is not well-documented. While drug-loaded nanoparticles can modulate microglial inflammation, their intrinsic biological effects on microglial activation are underexplored. We demonstrate that inhibiting endosomal acidification reduces pro-inflammatory microglial polarization, limits pathological engulfment of neurons, and reduces neuronal apoptosis. To achieve the same effects in vivo, building on a validated dual-site buffering mechanism of sulfonated chitosan, we develop sulfonated Nano Proton Scavengers (sNPS) as a materials-based strategy to modulate endo/lysosomal pH. After cerebral ischemia, sNPS showed greater fluorescence-associated enrichment in the ipsilateral than in the contralateral hemisphere and was associated with brain-resident and infiltrating immune-cell populations. In the injured brain, sNPS alleviated endo/lysosomal acid stress, suppressed TLR3/4-linked inflammatory signaling, and normalized inflammation-driven endo/lysosomal remodeling and proton-loading machinery, thereby restraining maladaptive microglial activation. This immunomodulation was accompanied by improved neural structural preservation and post-stroke survival and functional outcomes. These findings identify endosomal pH homeostasis as a tractable intracellular cue for material-driven immunoregulation and suggest that sNPS offers a complementary therapeutic direction for ischemic stroke.

Keywords:  endosomes; inflammation; ischemic stroke; microglia; toll‐like receptors

DOI:  https://doi.org/10.1002/advs.77311
J Clin Invest. 2026 Aug 18. pii: e200550. [Epub ahead of print]

Convection-enhanced delivery of dexamethasone in glioma models suppresses myeloid inflammation while avoiding systemic toxicities.

Nathaniel W Rolfe, Nicholas B Dadario, Liang Lei, Anthony Tang, Misha Amini, Damian E Teasley, Nkechime Ifediora, Peter Chabot, Nathan J Winans, Nina Yoh, Julia Furnari, Corina Kotidis, Clara H Stucke, Nivia M Urena, Yanping Sun, Abby Brand, Ashwin Viswanathan, Pavan Upadhyayula, Michael G Argenziano, Colin P Sperring, Nadine Khoury, Nelson Humala, Shikun Wang, Justin Neira, Peter A Sims, Brian J Gill, Peter Canoll, Jeffrey N Bruce.

  Dexamethasone is widely used to control cerebral edema and inflammation in glioblastoma, but its benefits are limited by systemic toxicities and adverse prognostic associations. We evaluated local administration of dexamethasone via convection-enhanced delivery (CED) to maximize intratumoral anti-inflammatory effects by increasing local corticosteroid exposure while minimizing systemic exposure. In two glioma mouse models, continuous intraparenchymal infusion of dexamethasone was well tolerated with no adverse effects. Pharmacokinetic analyses supported preferential intratumoral distribution and reduced systemic exposure with CED compared with systemic dosing. Single-nucleus RNA sequencing (snRNA-seq) and immunohistochemistry showed attenuation of glioma-associated inflammation with downregulation of reactive microglial/macrophage programs and reduced tumor-infiltrating myeloid cells with a morphology consistent with a less activated state. Experiments in human induced pluripotent stem cell (iPSC)-derived microglia confirmed that dexamethasone directly suppresses inflammatory gene expression, indicating a conserved mechanism across species. This inflammatory suppression was recapitulated in both immortalized microglial (HMC3) and macrophage (THP1) cell lines. These findings suggest that localized dexamethasone delivered by CED reprograms the glioma immune microenvironment and achieves control of inflammation without the systemic adverse effects associated with standard systemic dexamethasone therapy. This clinically translatable strategy may improve symptom management and provide a platform for integrating local immunomodulation with future glioblastoma therapies.

Keywords:  Brain cancer; Inflammation; Macrophages; Oncology

DOI:  https://doi.org/10.1172/JCI200550
Mol Biomed. 2026 Aug 18. pii: 141. [Epub ahead of print]7(1):

HMGB1 aggravates neuronal ferroptosis and microglial inflammation in metabolic syndrome-associated cognitive impairment via the NRF2-autophagic flux axis.

Xin Zhang, Yue Zhang, Meng-Meng Tang, Jia-Mei Zhang, Ya-Qin Xiao, Jian-Jun Yang, Cun-Ming Liu, Min Yu.

  Metabolic syndrome (MetS)-associated cognitive impairment is a growing global health crisis. The hippocampus is particularly vulnerable to metabolic stress, yet the precise molecular mechanisms linking systemic metabolic dysfunction to cognitive decline remain unclear. High-mobility group box 1 (HMGB1), a damage-associated molecule, is elevated in MetS. However, its specific role in simultaneously regulating hippocampal neuronal ferroptosis and microglial activation is poorly defined. Here we show that HMGB1 exacerbates MetS-associated cognitive impairment by promoting both neuronal ferroptosis and microglial inflammation. Using a high-fat high-glucose diet mouse model and primary co-cultures, we found that HMGB1 neutralization alleviated cognitive deficits, reduced neuronal ferroptosis, and suppressed microglial activation. Mechanistically, extracellular HMGB1 acts through neuronal toll-like receptor 4 (TLR4) to trigger the ubiquitination and degradation of nuclear factor erythroid 2-related factor 2 (NRF2). This HMGB1-induced loss of NRF2 impairs autophagic flux, thereby aggravating ferroptosis and neuroinflammation. Furthermore, in vitro conditioned medium experiments revealed a reciprocal pathological aggravation, where ferroptotic neurons and activated microglia both secrete HMGB1 to exacerbate each other's pathological state. These findings position HMGB1 as a pivotal mediator linking metabolic stress specifically to neuronal ferroptosis and neuroimmune activation. Targeting the HMGB1-NRF2-autophagic flux axis therefore offers a promising therapeutic strategy for mitigating cognitive impairment in patients with MetS.

Keywords:  Autophagic flux; Ferroptosis; HMGB1; Inflammation; Metabolic syndrome; NRF2

DOI:  https://doi.org/10.1186/s43556-026-00548-8
Mol Psychiatry. 2026 Aug 21.

Maternal sleep deprivation reshapes offspring hippocampal development through a Trem2-centered microglial program revealed by single-nucleus and spatial transcriptomics.

Xiaobin Wu, Liuqing Yang, Yepeng Fan, Xiaohuan Li, Xiuyu Shi, Chunfang Dai, Yayan Pang, Jiaojiao Wang, Yupeng Cun, Zhifang Dong.

Maternal sleep deprivation during late pregnancy is common and has been linked to increased neuropsychiatric risk in offspring, but the mechanisms by which it shapes developing hippocampal circuits remain unclear. The triggering receptor expressed on myeloid cells 2 (Trem2) is a key genetic risk factor for neurodegenerative disease and regulator of microglial survival and synaptic refinement, but it is unknown whether perinatal environmental stressors, such as maternal sleep loss, reprogram Trem2-associated microglial states in the developing hippocampus. Here, we combine single-nucleus RNA sequencing and spatial transcriptomics to generate a lifespan atlas of hippocampal cell populations in rat dams and offspring exposed to late-pregnancy maternal sleep deprivation (LSD) across postnatal day (P)1, 7, 14, and 56. LSD induces widespread, cell-type-specific transcriptional alterations across oligodendrocytes, astrocytes, and excitatory and inhibitory neurons, with a convergent and persistent disruption of microglial states characterized by downregulation of Trem2 and enrichment of gene modules shared with human neuropsychiatric and neurodegenerative risk loci. Behaviourally, LSD offspring display long-lasting deficits in Morris water maze performance, altered anxiety-related and exploratory behaviors in the open field and elevated plus maze, and impaired hippocampal long-term potentiation (LTP). AAV-mediated hippocampal Trem2 restoration, accompanied by recovery of Trem2 signal in Iba1-positive microglia, partially attenuates inflammatory remodeling and ameliorates LTP and behavioural abnormalities. Our findings identify maternal sleep deprivation as an early-life insult that programs a Trem2-centred microglial axis shaping hippocampal circuits and long-lasting cognitive and behavioral alterations, and suggest microglial Trem2 as a candidate target for mitigating neuropsychiatric risk associated with adverse sleep in pregnancy.

DOI: https://doi.org/10.1038/s41380-026-03831-w
Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2522958123

A human pluripotent stem cell triculture platform to elucidate microglial regulation of retinal ganglion cells in neuroinflammation.

Jade Harkin, Cátia Gomes, Reham Afify, Shruti V Patil, Shelby M Hetzer, Kaylee D Tutrow, Kiersten H Peña, Aaron Baker, Sailee S Lavekar, Kang-Chieh Huang, Jason S Meyer.

  Optic neuropathies, including glaucoma, are characterized by the progressive degeneration of retinal ganglion cells (RGCs), ultimately leading to irreversible vision loss. Increasing evidence implicates microglia, the resident immune cells of the central nervous system, as key modulators of RGC health and disease progression. However, the precise mechanisms by which microglia influence RGCs remain poorly understood, particularly in the human context. In this study, we established human pluripotent stem cell-derived coculture systems incorporating microglia, astrocytes, and RGCs to explore how microglia shape RGC growth and maturation under physiological conditions. We first examined the impact of homeostatic microglia on RGCs in both coculture and triculture systems, revealing distinct influences of cell types in coculture compared to when they were grown individually. We then modeled inflammatory states by activating microglia with lipopolysaccharide and evaluated their effects on RGCs both directly and in the context of astrocyte coculture. This stepwise, reductionist approach enabled us to dissect the cellular interactions driving RGC vulnerability in inflammatory conditions relevant to optic neuropathies. Our findings provide insight into the complex neuroimmune landscape that underlies RGC degeneration and identify key pathways that may serve as therapeutic targets across a range of optic nerve diseases.

Keywords:  microglia; neuroinflammation; retina; retinal ganglion cell; stem cell

DOI:  https://doi.org/10.1073/pnas.2522958123
Brain Behav Immun. 2026 Aug 18. pii: S0889-1591(26)00712-9. [Epub ahead of print]138 106964

β-Endorphin contributes to psychological stress- associated hippocampal microglial alterations and cognitive impairment.

Shanfeng Gao, Xia Wang, Lingyu Zhang, Yijie Li, Xuan Xiao, Yongxia Chang, Juan Yang.

  Psychological stress is a risk factor for cognitive impairment, yet the molecular mechanisms linking stress exposure to hippocampal dysfunction remain incompletely understood. β-Endorphin (β-EP), an endogenous opioid peptide, has been implicated in stress-related processes; however, its contribution to stress-associated cognitive impairment remains unclear. Using a chronic psychological stress model, we found that stressed rats exhibited anxiety- and depression-like behaviors, impaired learning and memory, reduced hippocampal neuronal plasticity, and altered microglial morphology and functional responses. These changes were accompanied by elevated β-EP levels in serum and hippocampal tissue and elevated hippocampal μ-opioid receptor (MOR) and δ-opioid receptor (DOR) expression. In vivo pharmacological studies showed that β-EP administration recapitulated several stress-associated alterations, whereas naloxone partially attenuated these alterations in stressed rats. Using BV2 cells as an exploratory model, β-EP exposure induced cellular alterations, including increased cell proliferation and phagocytic activity, and these changes were partially attenuated by naloxone and the selective MOR and DOR antagonists CTOP and NTI. Transcriptomic analysis and subsequent validation revealed increased NLRP3 inflammasome-related signaling in β-EP-treated BV2 cells, while pharmacological inhibition with the selective NLRP3 inhibitor MCC950 attenuated β-EP-associated cellular alterations. Collectively, these findings suggest that β-EP contributes to psychological stress-associated cognitive deficits in association with opioid receptor signaling and microglial alterations, and suggest NLRP3 inflammasome-related signaling as a potential pathway involved in β-EP-associated cellular responses.

Keywords:  Cognitive impairment; Microglia; NLRP3 inflammasome; Opioid receptors; Psychological stress; β-Endorphin

DOI:  https://doi.org/10.1016/j.bbi.2026.106964
Cell Rep. 2026 Aug 17. pii: S2211-1247(26)00912-5. [Epub ahead of print]45(8): 117834

Circadian rhythms in microglia mediate early life synaptic development in a sex-specific manner.

Brandy N Routh, Cecily R Gibson, Celina C Yang, Leanna Doan, Andrew D Gaudet, Hans A Hofmann, Regina A Mangieri, Laura K Fonken.

  Children today experience widespread circadian disruption from nighttime screen use and irregular sleep, yet how internal clocks shape brain development is unclear. Adolescence is a critical window when synaptic connectivity is refined, in part by microglia that engulf synaptic elements. Here, in adolescent mice, we show that hippocampal microglia exhibit diurnal transcriptional rhythms, with synaptic pruning gene expression peaking during the rest phase. Inducible deletion of the core clock gene Bmal1 in microglia in early life abolishes these rhythms and alters developing hippocampal synapses in a sex-dependent manner. In males, clock disruption increases synapse engulfment, reduces dendritic spine density, and decreases synaptic connectivity; females show similar reductions in synaptic connectivity without overt postsynaptic structural changes. Microglial clock disruption also induces broad, sex-specific changes in synapse-related gene expression that overlap with neurodevelopmental disorder pathways and lead to impaired memory and sociability, indicating microglial clocks as key regulators of developmental synapse refinement.

Keywords:  Bmal1; CP: developmental biology; CP: neuroscience; adolescence; brain development; circadian rhythms; hippocampus; microglia; neurodevelopmental disorders; synapse; synaptic pruning

DOI:  https://doi.org/10.1016/j.celrep.2026.117834
Acta Pharmacol Sin. 2026 Aug 17.

BDKRB2 upregulation by dystrophic microglia drives pain hypersensitivity in aged mice.

An Liu, Ming-Jun Zhang, Jin-Rong Guo, Han Chu, Song-Bin Liu, Dan-Yang Chen, Yuan-Zhong Kai, Peng Cao, Zhi Zhang.

  Although pain sensitization is among the most common conditions affecting the elderly, its underlying neural mechanisms remain unclear. Here, we found that mechanical hypersensitivity arises from enhanced glutamatergic excitability in primary somatosensory cortex due to bradykinin receptor B2 (BDKRB2) upregulation by dystrophic microglia during aging. Specifically, in vivo fiber photometry in aged mice revealed hyperactivity of glutamatergic neurons in primary somatosensory cortex of hindlimb (S1HLGlu), while chemogenetic inhibition of these neurons reverses pain hypersensitivity in aged mice. BDKRB2 expression on S1HLGlu neurons is significantly increased in aged mice, whereas its conditional knockdown restores pain sensitization, and its overexpression leads to nociceptive hypersensitivity in young mice. Moreover, chemogenetic or pharmacological inhibition of dystrophic microglia in aged mice reduces BDKRB2 levels, alleviating pain hypersensitivity. The present study thus demonstrates that microglia-mediated S1HLGlu hyperactivity drives development of aging-related pain via BDKRB2 signaling, suggesting several potentially effective therapeutic targets for treating geriatric pain.

Keywords:  BDKRB2; aging, pain; microglia; somatosensory cortex

DOI:  https://doi.org/10.1038/s41401-026-01907-5
Genes Dis. 2026 Nov;13(6): 101969

Spatial transcriptomics revealed the regulatory role of CCN1 to microglia distribution through region-specific cellular interactions.

Zhile Bai, Zhanhe Chang, Shuguang Wang, Jiangli Zheng, Huan Wu, Hanyu Liu, Yalin Zhang, Jiayang Xie, Qingran Bai, Jiqing Yin, You Wu, Qin Shen, Shaorong Gao, Yawei Gao.

  During brain development, neural stem progenitor cells (NSPCs) and microglia interact within precise spatial niches; however, decoding mechanism is full of challenges using traditional analytical techniques. Here, we investigated the role of CCN1, a secreted protein enriched in NSPCs, using CNS-specific Ccn1 knockout mice. Through single cell RNA-seq analysis, we found that microglia were significantly reduced in the ventricular zone (VZ) at E17.5 and P2, with elevated expression of autophagy- and activation-related genes in Ccn1-CKO mice. Spatial transcriptomics at P2 further showed that Ccn1 deletion region-specific redistributes microglia and leads to increased microglial aggregation and activation in the rostral lateral septum (LSR), alongside reductions in the VZ. Mechanistically, Ccn1 deletion in NSCs led to region-specific dysregulation of the key signaling ligands, Csf1 and Il2. We found the elevated expression of Csf1 and Il2 specifically within the LSR region, which corresponded to the up-regulation of their respective receptors (Csf1r, Cd53) and downstream targets (Spp1, Ctsb) in LSR microglia, affecting microglial status. Our study reveals a region-specific NSC-microglia interaction regulated by Ccn1, offering a new paradigm for understanding multicellular dynamics in brain development.

Keywords:  Ccn1; Cellular regional interactions; Microglia; Neural stem cells; Spatial transcriptomics

DOI:  https://doi.org/10.1016/j.gendis.2025.101969
Sci Signal. 2026 Aug 04. 19(949): eaea4402

Adenosine 2A receptor drives microglial efferocytosis to accelerate white matter repair and functional recovery after stroke.

Yan Deng, Qian He, Bolin Yao, Xiang Chen, Guangli Cheng, Minhua Xu, Jiachun Hu, Luis Graca, Xiao Zhu, Xiao-Yong Zhang, Yan You, Cong Li.

Although reperfusion therapy effectively restores blood flow to occluded brain arteries after ischemic stroke, many patients develop persistent white matter injury, a major contributor to long-term neurological disability. Currently, there are few approved clinical therapies that specifically target white matter repair to enhance functional recovery after stroke. We demonstrated that microglial adenosine 2A receptor (A2AR) is essential for spontaneous white matter regeneration after ischemic injury in mice. Deletion of A2AR in microglia specifically impaired chronic-phase repair without altering the severity of acute ischemic injury. Pharmacological activation of A2AR signaling with blood-brain barrier-permeable agonistic micelles during the early reperfusion phase enhanced white matter structural repair and led to sustained improvements in cognitive and sensorimotor function in mice. Mechanistically, A2AR activation promoted microglial efferocytosis of apoptotic cells and myelin debris in the lesioned white matter, thereby limiting secondary necrosis-induced inflammation, enhancing neurotrophic factor release, and establishing a reparative microenvironment conducive to oligodendrocyte precursor cell differentiation and remyelination. Moreover, A2AR signaling engaged HIF1α-dependent metabolic reprogramming to increase glycolysis, thereby providing the energetic support required for efficient and sustained efferocytosis. Together, these findings identify A2AR as a critical regulator of microglia-mediated white matter repair and a promising therapeutic target for enhancing regeneration after stroke.

DOI: https://doi.org/10.1126/scisignal.aea4402
Front Immunol. 2026 ;17 1858954

Gut-derived small extracellular vesicles support trained innate immune tolerance in murine microglial cells.

Trim Lajqi, Natascha Köstlin-Gille, Cahit Birdir, Janine Hebel, Ilir Miftari, Reinhard Bauer, Sotirios G Zarogiannis, Charlotta Funaya, Christian Gille, Stefanie Dietz-Ziegler.

   Introduction: Microglia are the resident immune cells of the central nervous system (CNS) that maintain tissue homeostasis and contribute to the pathogenesis of neuroinflammatory disorders. As innate immune cells, microglia can acquire memory-like states that exert long-term effects on CNS function and disease susceptibility. Increasing evidence highlights a dynamic interaction between the gut microbiota and the CNS, shaping microglial maturation and responsiveness throughout life. In addition to soluble microbial metabolites, gut-derived extracellular vesicles (EVs), including vesicles of microbial origin, have emerged as important mediators of microbiota-host communication capable of modulating brain homeostasis and inflammatory signaling; however, their role in programming microglial immune memory remains unclear.
Methods: Here, we examined whether gut-derived small EVs influence memory-like features of primary murine microglia in vitro. Microglia were primed with small EVs followed by a secondary lipopolysaccharide (LPS) challenge, and inflammatory signaling, metabolic activity, epigenetic markers, and effector functions (migration and phagocytosis) were assessed.
Results: Small EV priming followed by secondary LPS challenge induced a trained innate immune tolerance phenotype characterized by reduced pro-inflammatory mediator release and attenuated TLR2/4-MyD88-p38 MAPK signaling. This tolerant state was accompanied by suppressed glycolytic activity and decreased levels of activating histone H3 marks, indicating coordinated metabolic and epigenetic reprogramming. Notably, despite diminished inflammatory signaling, small EV-primed microglia displayed enhanced migratory and phagocytic capacities associated with increased ERK1/2 activation.
Discussion: Together, these findings indicate that gut-derived small EVs can imprint memory-like programs in microglia that restrain inflammatory activation while preserving essential effector functions in vitro, suggesting a mechanism by which microbiota-brain communication may shape neuroinflammatory responses.

Keywords:  epigenetics; extracellular vesicles; gut; inflammation; metabolism; microglia; migration; phagocytosis

DOI:  https://doi.org/10.3389/fimmu.2026.1858954
Stem Cell Reports. 2026 Aug 20. pii: S2213-6711(26)00264-X. [Epub ahead of print] 103053

Development and validation of a long-term co-maturation protocol for human stem cell-derived microglia and neuronal networks.

Annika Mordelt, Imke M E Schuurmans, Nicky Scheefhals, Marina P Hommersom, Koen Slottje, Kimberly Mast, Mara Graziani, Carlos O González, Klaas W Mulder, Laura J A Wingens, Dirk Schubert, Nael Nadif Kasri, Lot D de Witte.

  Microglia-neuron interactions play a key role in a variety of central nervous system disorders. Technologies using human induced pluripotent stem cells (hiPSCs) have been developed to model human brain cells with the goal to understand their function. To effectively study neuro-immune crosstalk and investigate microglial contributions to neuronal network development and function, both microglia and neurons should co-mature allowing for long-term interactions throughout their differentiation. Here, we present a co-maturation protocol that robustly generates glutamatergic neuronal networks containing hiPSC-derived microglia. We validated the long-term co-cultures using single-cell transcriptomics, imaging, and neuronal activity readouts. In this protocol, astrocytes were required for long-term survival of microglia and for their integration into neuronal networks. Our co-maturation approach induced the typical ramified microglia morphology and characteristic microglia-neuron interactions. Homeostatic markers such as P2RY12 and TMEM119 and neuronal remodeling-associated genes were upregulated compared to microglia monocultures, highlighting the necessity of the environment to generate and maintain the context-dependent microglia signature in vitro. In this manuscript, we include the full optimization process of our co-maturation approach, a comprehensive description of the protocol, practical guidelines, and troubleshooting tips. Our co-maturation model provides a powerful tool to assess the role of human microglia in modulating neuronal function and development in health and disease.

Keywords:  co-culture; differentiation; iPSC; long-term; microglia; neuro-immune interactions; neuron-microglia communications; neurons; protocol

DOI:  https://doi.org/10.1016/j.stemcr.2026.103053
Exp Neurol. 2026 Aug 19. pii: S0014-4886(26)00351-1. [Epub ahead of print] 115985

Loss of PHD3 rescues mice from Neuroinflammation and cognitive disorders induced by lipopolysaccharide or surgical trauma.

Ji Che, Yixu Deng, Xiang Zhang, Changsheng Shi, Zhiyong He, Jing Dong, Jun Zhang.

   OBJECTIVE: Neuroinflammation is recognized as a contributing factor to cognitive disorders. Previous studies have demonstrated PHD3 drives microglia-mediated neuroinflammation. Present study aims to further clarify the role of PHD3 in both lipopolysaccharide (LPS)- and anesthesia/surgery (AS)-induced neuroinflammation and cognitive impairments.
METHODS: Eight-week-old male wild-type and PHD3 knockout C57BL/6 J mice were used to establish LPS- and AS-induced neuroinflammation models. Cognitive function was evaluated using the Y-maze, open-field, and novel object recognition tests. Neuroinflammatory responses, microglial activation, synaptic proteins, and apoptosis-associated changes in the hippocampus and prefrontal cortex were assessed by Western blotting and immunofluorescence staining. Furthermore, an adeno-associated virus (AAV)-mediated conditional microglial PHD3 knockdown model was established to investigate the role of microglial-specific PHD3 in neuroinflammatory regulation.
RESULTS: PHD3 knockout significantly ameliorated LPS- and AS-induced cognitive deficits, accompanied by reduced expression of pro-inflammatory mediators TNF-α and IL-1β, and decreased the activation of NF-κB pathway in the hippocampus and prefrontal cortex. PHD3 deficiency also attenuated microglial activation, restored postsynaptic density protein 95 (PSD95) and Synapsin I ‌(SYN1) levels, and reduced neuronal proapoptotic activation. Mechanistically, conditional microglial PHD3 knockdown recaptured the anti-inflammatory effects observed in PHD3 knockout mice via reducing LPS-induced inflammatory cytokines production, suppressing IKK/IκBα/NF-κB signaling activation, and modulating expressions of microglial activation-associated markers iNOS/CD86 and CD206/Arg-1. In addition, conditional microglial PHD3 knockdown attenuated LPS-induced upregulation of HIF-1α rather than HIF-2α expression.
CONCLUSION: Our results demonstrate that PHD3 deficiency exerts neuroprotective effects against systemic inflammation-induced cognitive dysfunction by suppressing microglial activation, synaptic damages, and neuronal apoptosis may through NF-κB signaling. These findings suggest that PHD3 may represent a promising therapeutic target for inflammation-associated cognitive disorders.

Keywords:  Cognitive impairment; Lipopolysaccharide; Neuroinflammation; Prolyl hydroxylase 3; Surgery

DOI:  https://doi.org/10.1016/j.expneurol.2026.115985
ACS Chem Neurosci. 2026 Aug 19. 17(16): 3082-3093

Phage Display-Derived Cyclic Peptides Target TREM2 and Modulate Microglial Responses Under Amyloid Stress.

Natalie Fuchs, Shaoren Yuan, Katarzyna Kuncewicz, Mohamed Atta Elhamouly, Farida El Gaamouch, Moustafa T Gabr.

  Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function and a promising therapeutic target in Alzheimer's disease. While current strategies have largely focused on antibody-based agonists, alternative modalities capable of modulating TREM2 signaling remain underexplored. Here, we report the discovery of TREM2-binding cyclic peptides using a disulfide-constrained phage display library. Screening and biophysical validation identified multiple binders, with TREM2-6 and TREM2-12 exhibiting micromolar affinity. Both peptides modulated microglial responses in human iPSC-derived model of amyloid stress and in neuron-microglia cocultures. Molecular dynamics simulations supported stable peptide-TREM2 interactions, with TREM2-12 displaying a more constrained binding mode. In vitro pharmacokinetic profiling revealed favorable plasma and intestinal stability but limited permeability, consistent with cyclic peptide scaffolds. Together, these findings establish cyclic peptides as a viable modality for targeting TREM2 and provide a foundation for the development of tunable neuroimmune therapeutics.

Keywords:  Alzheimer’s disease; TREM2; microglia; peptides; phage display

DOI:  https://doi.org/10.1021/acschemneuro.6c00304
J Immunol. 2026 Aug 04. pii: vkag223. [Epub ahead of print]215(8):

KDM4A promotes microglial pyroptosis and neuropathic pain via the MEG3/SMURF2/HES1 axis.

Na Wang, Shihua Yu, Lixia Chen, Jinlong Yang, Yujie Kou, Xuesong Sun.

  Neuropathic pain (NP) is a refractory clinical disorder in which microglial pyroptosis plays a crucial role, yet the epigenetic regulation by lysine demethylase 4A (KDM4A) remains unclear. In this study, chronic constriction injury (CCI) rat models were established, and KDM4A was knocked down to evaluate its effects on paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), histopathological changes, and NLR family pyrin domain containing 3 (NLRP3)/ionized calcium-binding adapter molecule 1 (Iba1) expression. In vitro, lipopolysaccharide (LPS)-treated BV2 microglial cells were used as an inflammatory model. We found that KDM4A and the long non-coding RNA maternally expressed gene 3 (MEG3) were highly expressed in NP rats. KDM4A inhibition ameliorated CCI-induced symptoms and suppressed microglial pyroptosis in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assays revealed that KDM4A promoted MEG3 expression by removing histone H3 lysine 9 di-/trimethylation (H3K9me2/3) modifications at the MEG3 promoter. RNA immunoprecipitation (RIP) and co-immunoprecipitation (Co-IP) assays further demonstrated that MEG3 at least partially recruited the E3 ubiquitin ligase SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) to bind hairy and enhancer of split 1 (HES1), promoting HES1 ubiquitination and degradation. Rescue experiments confirmed that overexpression of MEG3 or SMURF2 partially reversed the inhibitory effect of KDM4A knockdown on microglial pyroptosis in vitro. In conclusion, KDM4A facilitates microglial pyroptosis and aggravates pain responses in NP rats through the MEG3/SMURF2/HES1 axis in a manner at least partially dependent on SMURF2, providing novel insights into the epigenetic regulation of NP.

Keywords:  KDM4A; MEG3; NLRP3 inflammasome; microglial pyroptosis; neuropathic pain

DOI:  https://doi.org/10.1093/jimmun/vkag223