bims-microg 2026-08-09 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–08–09
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.
Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors.
A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.
Disrupting galectin-3 and NET-mediated microglia-neutrophil cross-talk suppresses pathological retinal angiogenesis.
Loss of SHP1 in Spinal Astrocytes Triggers T-Lymphocyte Infiltration and Nociceptive Hypersensitivity.
Microglial 5-LOX-activating protein antagonism alleviates leukotriene-driven neuroinflammation.
Targeting microglial MyD88 reprograms injury-activated microglia and promotes spinal cord repair via TGF-β signaling and biomimetic nanodelivery.
Endothelial epigenetic senescence driven microglial activation mediates cardio-retinal neuroinflammation in heart failure.
Neuroinflammation as molecular landscape of post-operative delirium revealed by live human brain multi-omics profiling.
Maternal Stress Primes Adolescent Stress Susceptibility via Microglial Complement-Dependent Synaptic Phagocytosis.
FKBP5 Orchestrates a Biphasic Microglial Response in Spinal Cord Injury by Sequentially Activating the GPR84/IL-1β Pathway and the LDHA-Lactylation-FXYD5/LGALS1 Axis.
Microglial SREBP2 regulate cholesterol-related lipid metabolism and inflammatory levels following ischemic stroke via the autophagy pathway.
Multispectral photoacoustic microscopy and NIR-II fluorescence imaging of TREM2-positive microglia in Aβ-driven Alzheimer's pathogenesis.
Single-Nucleus Transcriptomics Identifies Microglial Interferon Regulatory Factor 5 as a Regulator of Neuroinflammation During Heart Failure Progression After Myocardial Infarction in Rats.
Microglial CX3CR1 signaling mediates synaptic pruning in degenerative cervical myelopathy.
Sex-dependent protective effects of microglial tumor necrosis factor on post-stroke inflammation and myelin injury.
Predicting Relevant Microglia-Associated Cell-Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1.
Gq Signaling in Microglia Triggers Interferon Responses and Improves Outcome After Ischemic Stroke.
GPR146 Deficiency Enhances Microglial Phagocytosis and Blood-Brain Barrier-Associated Markers in an Acute Amyloid-β Model.
Single-cell analysis of the human retina reveals stage-linked microglial states and neural-immune circuit rewiring in diabetic retinopathy.

Immunity. 2026 Aug 03. pii: S1074-7613(26)00307-9. [Epub ahead of print]

Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.

Christopher D Balak, Johannes C M Schlachetzki, Addison J Lana, Elizabeth West, Christine Hong, Jordan DuGal, Yi Zhou, Benjamin Li, Nathanael J Spann, Payam Saisan, Vishal Sarsani, Kilian L Kleemann, Xiaoming Zhang, Martina P Pasillas, Sydney O'Brien, Juliette A Bokor, Philip L S M Gordts, Oleg Butovsky, Beth Stevens, Fredrik Kamme, Christopher K Glass.

  Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice. Further investigation identified dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors. Features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency were also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer's disease patients. These findings reveal common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.

Keywords:  ChIP-seq; MITF; MPS-IIIA; TFE3; disease-associated microglia; epigenetics; lysosomal storage disorder; lysosome; microglia; neurodegeneration

DOI:  https://doi.org/10.1016/j.immuni.2026.07.008
Immunity. 2026 Aug 03. pii: S1074-7613(26)00308-0. [Epub ahead of print]

Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors.

Leon Tejwani, Catherine M Heffner, Christopher Balak, Lukas L Skuja, David Tatarakis, Anil Rana, Seungyoon B Yu, Gabriel A Fitzgerald, Connie Ha, Gabrielly Lunkes de Melo, Elizabeth W Sun, Matthew J Simon, Jason C Dugas, Johann Chow, Elliot Thomsen, Lily Sarrafha, Eric Liang, Neal Gould, Jung Suh, Thomas Sandmann, Christopher K Glass, Gilbert Di Paolo.

  Lysosomal dysfunction in myeloid cells is increasingly implicated in neurodegenerative diseases. To examine the interplay between lysosomal health and cellular state, we performed multi-omic profiling of myeloid cells from brains of aged mice lacking progranulin (Grn-/- mice), a lysosomal protein linked to neurodegeneration. Single-cell RNA sequencing identified a microglial subpopulation defined by GPNMB expression, which displays hallmarks of lysosomal stress, including altered lysosomal protein expression, lipofuscinosis, and metabolic and lipid dysregulation. Epigenetic profiling of Grn-/- microglia revealed an enrichment of MITF/TFE transcription factor motifs at active enhancers, and deletion of these factors reversed the Grn-/--specific myeloid cell transcriptional signature. Diverse lysosomal perturbations drove a common transcriptional and functional signature, with conditions that induce lysosomal deacidification closely phenocopying progranulin deficiency. Finally, compensatory GPNMB induction in Grn-/- myeloid cells promoted lysosomal acidification, and loss of myeloid cell GPNMB exacerbated neurotoxicity. Our findings link lysosomal health with epigenetic, transcriptional, and functional myeloid cell states associated with neurodegeneration.

Keywords:  disease-associated microglia; epigenetics; frontotemporal dementia; granulin; lipids; lipofuscin; lysosomal pH; lysosomes; macrophages; microglia

DOI:  https://doi.org/10.1016/j.immuni.2026.07.009
Nat Neurosci. 2026 Aug 04.

A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.

Julien Klimmt, Carolina Cardoso Gonçalves, Jessica Valentina Montgomery, Stephan A Müller, Merle Bublitz, Severin Filser, Lars Paeger, Brigitte Nuscher, Angelika Dannert, Sigrun Roeber, Veronica Pravata, Martina Schifferer, Joshua J Shrouder, Nathalie Schulz, Judit González-Gallego, Silvia Cappello, Thomas Misgeld, Nikolaus Plesnila, Eduardo Beltrán, Jochen Herms, Elena De Domenico, Marc D Beyer, Joachim L Schultze, Christian Haass, Stefan F Lichtenthaler, Caterina Carraro, Dominik Paquet.

Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer's disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer's disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.

DOI: https://doi.org/10.1038/s41593-026-02367-0
Sci Transl Med. 2026 Aug 05. 18(861): eaea5661

Disrupting galectin-3 and NET-mediated microglia-neutrophil cross-talk suppresses pathological retinal angiogenesis.

Ziyi Zhou, Tianhao Yuan, Jiaxing Sun, Chaowei Tian, Guoheng Zhang, Yifan Fang, Yuan Chen, Yixuan Xi, Jiayi Kong, Xiaojia Sun, Tianfang Chang, Zifeng Zhang, Xuri Li, Yusheng Wang, Guorui Dou.

Current research on pathological retinal neovascularization primarily focuses on growth factors, inflammation, and endothelial signaling pathways. However, increasing attention is being directed toward disruptions in the retinal immune microenvironment. Therefore, deciphering the immune-angiogenic interplay could uncover therapeutic avenues for neovascular disorders. Through integrative analyses of single-cell RNA sequencing from human fibrovascular membranes and multicohort clinical datasets, we identified neutrophil infiltration as an independent risk factor for diabetic retinopathy progression. Mechanistically, activated microglia preceded and potentiated neutrophil infiltration by secreting galectin-3 (GAL3), establishing a self-amplifying feedback loop that sustained microglial activation and drove pathological angiogenesis in mice with oxygen-induced retinopathy (OIR). To therapeutically disrupt this loop, we engineered a photocurable hydrogel for the sustained intravitreal delivery of GAL3 and vascular endothelial growth factor (VEGF)-neutralizing antibodies, which effectively suppressed aberrant angiogenesis in mice with OIR. Together, these findings reinforce the concept of retinal neovascularization as an immunovascular disorder and underscore the therapeutic potential of microenvironment-modulating strategies using biomaterials.

DOI: https://doi.org/10.1126/scitranslmed.aea5661
Adv Sci (Weinh). 2026 Aug 03. e76932

Loss of SHP1 in Spinal Astrocytes Triggers T-Lymphocyte Infiltration and Nociceptive Hypersensitivity.

Lan-Xing Yi, Lin Yang, Kang-Li Wang, Hui-Zhu Liu, Rui-Ying Chen, Min Su, Xiao Xiao, Yu-Qiu Zhang.

  Chronic pain is sustained by complex neuroimmune interplay within the spinal cord, yet how astrocytes constrain immune amplification remains poorly understood. Here we identified Src-homology 2 domain-containing protein tyrosine phosphatase-1 (SHP1; encoded by Ptpn6) as a key suppressor of spinal neuroinflammation and nociceptive hypersensitivity. Astrocyte-specific SHP1 deletion in the spinal dorsal horn induced profound astrocytic morphological changes, increased C-X-C motif chemokine ligand 10 (CXCL10) expression, disrupted blood-brain barrier (BBB) integrity, and facilitated the infiltration of activated T lymphocytes into the spinal parenchyma. These infiltrating T cells promoted microglial activation, enhanced excitatory synaptic transmission, increased the excitability of somatostatin (SOM)-positive neurons, and ultimately triggered nociceptive hypersensitivity. Mechanistically, T cell recruitment was governed by an SHP1-dependent regulatory circuit, in which SHP1-mediated Signal transducer and activator of transcription 1 (STAT1) dephosphorylation restrained Cxcl10 transcription. Blocking the STAT1-CXCL10-CXCR3 signaling axis alleviated T cell infiltration and nociceptive hypersensitivity. Notably, we found that during the development of neuropathic pain, spinal SHP1 expression was significantly downregulated, accompanied by upregulation of CXCL10. Overexpression of SHP1 in astrocytes markedly attenuated astrocyte activation and alleviated mechanical allodynia induced by spared nerve injury (SNI). Collectively, our findings revealed an astrocyte-defined immune checkpoint that restrains neuroinflammatory escalation and pain persistence, emphasizing SHP1 as a promising therapeutic target for chronic pain.

Keywords:  CXCL10/CXCR3; SHP1; T cell infiltration; allodynia; astrocyte; blood‐brain barrier

DOI:  https://doi.org/10.1002/advs.76932
Acta Neuropathol. 2026 Aug 04. pii: 16. [Epub ahead of print]152(1):

Microglial 5-LOX-activating protein antagonism alleviates leukotriene-driven neuroinflammation.

Julia Konings, Fleur Mingneau, Serhii Chornyi, Cathrin E Hansen, Rianne T M van der Brugt, Tessa G van Elk, Laura Bolkaerts, Bo Batens, Gábor Tóth, Ingela Lanekoff, Frédéric M Vaz, Alessio Cardilli, Marie Sels, Susanne M A van der Pol, Helga E de Vries, Martin Giera, Oliver Werz, Sofie Kessels, Sanne G S Verberk, Jeroen F J Bogie, Merel Rijnsburger, Jerome J A Hendriks, Gijs Kooij.

  In multiple sclerosis (MS), the chronic, unresolved nature of neuroinflammation within the central nervous system (CNS) remains a major obstacle for effective therapeutic intervention. This challenge arises primarily due to an incomplete understanding of the dysregulated inflammatory and pro-resolving pathways underlying MS lesion progression. Bioactive lipid mediators (LMs), biosynthesized through the coordinated actions of specific enzymes like lipoxygenases (LOX) and cyclooxygenases (COX), are key regulators of both the initiation and resolution of an inflammatory response; however, their spatial organization and functional role during MS pathology have not been fully elucidated. Here, by using pneumatically assisted nanospray desorption electrospray ionization (PA nano-DESI) mass spectrometry imaging and immunohistochemistry, we reveal an increase in the LM leukotriene B4 (LTB4) in human MS white matter compared to controls, with further enrichment in MS lesions relative to perilesional areas, alongside elevated microglial 5-LOX activating protein (FLAP) expression. Pharmacological antagonism of FLAP suppresses LTB4 biosynthesis in human-induced pluripotent stem cell (iPSC)-derived microglia with only marginal effects on the microglia transcriptional phenotype as determined by RNA sequencing. Moreover, in vivo FLAP antagonism ameliorates disease severity and spinal cord inflammatory gene expression in the experimental autoimmune encephalomyelitis (EAE) model, an animal model of MS, in both a prophylactic and therapeutic settings. This coincided with reduced local LTB4 biosynthesis and reduced levels of inflammatory monocytes within the spinal cord during EAE. Together these findings establish the FLAP/LTB4 axis as a driver of neuroinflammation and a druggable therapeutic target for chronic inflammatory CNS disorders like MS.

Keywords:  5-Lipoxygenase activating protein (FLAP); Experimental autoimmune encephalomyelitis (EAE); Leukotriene B4 ; Lipidomics; Microglia; Multiple sclerosis; Neuroinflammation; PA nano-DESI MSI,

DOI:  https://doi.org/10.1007/s00401-026-03055-w
Theranostics. 2026 ;16(14): 8017-8035

Targeting microglial MyD88 reprograms injury-activated microglia and promotes spinal cord repair via TGF-β signaling and biomimetic nanodelivery.

Jintao Liu, Beibei Yu, Wanjun Cao, Jilu Liu, Yundi Gao, Honghui Mao, Xiaochuan Gao, Lingli Guo, Shengyou Li, Qiao Huang, Mingze Qin, Fang Kuang, Jinghui Huang.

   Background: Following spinal cord injury (SCI), activated microglia sustain neuroinflammation and drive secondary tissue damage, and this limits functional recovery. Myeloid differentiation primary response 88 (MyD88) is a central adaptor of innate immune signaling, but whether and how microglial MyD88 regulates state transition after SCI remains unclear. This study aims to explore the impact of microglial MyD88 signaling on microglial state trajectories and tissue repair after SCI and to develop a microglia-targeted delivery strategy for therapeutic modulation.
Methods: A forceps-mediated SCI mouse model was established, and bulk and single-cell RNA sequencing were used to profile the temporal activation of microglial MyD88 signaling in the spinal cord. Pharmacological MyD88 inhibition (ST2825) and inducible microglia-specific MyD88 conditional knockout mice (Tmem119 CreERT2;Myd88 fl/fl) were used to assess neuroinflammation, tissue remodeling and downstream signaling. Functional recovery was evaluated by behavioral testing, bidirectional axonal tracing and electrophysiology. For translational validation, microglia membrane-coated, peptide-modified biomimetic nanoparticles (ST2825·DSPE@MG) were engineered to enhance microglia targeting and therapeutic efficacy.
Results: Transcriptomic analyses revealed rapid and sustained activation of MyD88 signaling preferentially in microglia after SCI. ST2825 suppressed pro-inflammatory outputs in vitro and in vivo while preserving trophic mediators. Microglia-specific MyD88 deletion reprogrammed injury-activated microglia from a pro-inflammatory state to a repair-associated phenotype, reducing neuronal damage, preserving axons and improving locomotor recovery. TGF-β receptor blockade with LY2109761 abolished the protective effects of MyD88 deficiency. Additionally, ST2825·DSPE@MG nanoparticles exhibited microglia-targeted uptake and conferred superior therapeutic efficacy.
Conclusion: Our data establish MyD88 as a critical regulator of microglial reprogramming after SCI and highlight its potential as a therapeutic target for spinal cord repair.

Keywords:  MyD88; TGF-β; biomimetic nanoparticle; microglial state transition; spinal cord injury

DOI:  https://doi.org/10.7150/thno.136733
Theranostics. 2026 ;16(14): 8055-8076

Endothelial epigenetic senescence driven microglial activation mediates cardio-retinal neuroinflammation in heart failure.

Mengdan Wang, Shuo Zhang, Tursunjan Aziz, Shiyao Zhang, Xiao Wu, Gang Li, Yan Wang.

   Rationale: Heart failure (HF) is increasingly recognized as a systemic disorder that extends beyond the heart and affects neurovascular tissues, including the retina. However, the mechanisms by which circulating factors from HF trigger retinal neuroinflammation remain unclear.
Methods: HF was induced in adult mice by transverse aortic constriction (TAC). Retinal structure and function were evaluated using optical coherence tomography (OCT) and electroretinography (ERG). Parabiosis and plasma transfer experiments were performed to assess the role of circulating factors. Endothelial senescence, microglial activation, and inflammatory signaling were analyzed using immunofluorescence, qPCR, and molecular assays. The functional relevance of TGFβ2 and microglia was tested using anti-TGFβ2 antibody administration and microglial depletion with PLX5622 treatment.
Results: TAC mice exhibited pronounced retinal thinning, diminished electroretinography (ERG) amplitudes, and reduced vascular density. Exposure of healthy mice to HF plasma reproduced these abnormalities, indicating that circulating mediators drive retinal injuries. TGFβ2 levels were markedly elevated in the plasma of both patients with HF and TAC mice. Mechanistically, TGFβ2 activated the pSMAD2/EP300 pathway in retinal endothelial cells, promoting H3K9 acetylation, P21 induction, and endothelial cell senescence. Senescent endothelial cells release proinflammatory factors that activate retinal microglia, leading to hypertrophic morphology, enhanced synaptic phagocytosis, and upregulation of cytokines such as IL1β, TNFα, and IL6. Neutralization of TGFβ2 or microglial depletion markedly reduced inflammation, preserved the retinal architecture, and restored visual function.
Conclusions: Elevated TGFβ2 levels in heart failure drive retinal endothelial epigenetic senescence, which secondarily activates microglia and induces neuroinflammation. Endothelial-specific disruption of TGFβ2 signaling is sufficient to protect the retina independently of primary cardiac recovery. Targeting the TGFβ2-endothelial-microglia axis may represent a promising therapeutic strategy for preventing retinal neurovascular degeneration associated with systemic cardiac disease.

Keywords:  TGFβ2; epigenetic senescence; heart failure; microglia activation; neuroinflammation

DOI:  https://doi.org/10.7150/thno.136220
Mol Psychiatry. 2026 Aug 05.

Neuroinflammation as molecular landscape of post-operative delirium revealed by live human brain multi-omics profiling.

Takaya Ishii, Tao Wang, Kazuki Shibata, Shota Nishitani, Takehiko Yamanashi, Nadia E Wahba, Tomoteru Seki, Kaitlyn J Thompson, Kyosuke Yamanishi, Tsuyoshi Nishiguchi, Akiyoshi Shimura, Bun Aoyama, Nipun Gorantla, Nathan J Phuong, Hieu D Nguyen, Therese A Santiago, Yoshitaka Nishizawa, Takaaki Nagao, Mathew A Howard, Hiroto Kawasaki, Kyosuke Hino, Atsushi Ikeda, Michael P Snyder, Gen Shinozaki.

Post-operative delirium (POD) is a serious complication of surgery particularly in older adults, characterized by acute disturbances in consciousness and cognition and associated with increased mortality and long-term cognitive impairment. Despite its clinical relevance, the underlying pathophysiology remains poorly understood. To address this, we performed multi-omics profiling of live brain tissue from patients undergoing neurosurgery. Single-nucleus RNA sequencing revealed POD-specific transcriptional alterations in glial cells, especially microglia, characterized by enhanced neuroinflammatory signatures. Astrocytes also exhibited changes in synaptic and migratory pathways. Upstream analysis implicated external cytokines as potential drivers of glial responses, while downstream analysis linked POD to encephalitis and dementia. DNA methylation profiling identified immune-related epigenetic alterations, suggesting a regulatory role in POD-associated neuroinflammation. Integration of bulk methylation and cell type-specific transcriptomic data suggested that epigenetic changes may influence gene expression during POD pathogenesis. These findings provide the convincing evidence of neuroinflammation and glial involvement as the pathophysiological mechanism of POD based on the first multi-omics analysis using patient brain tissue.

DOI: https://doi.org/10.1038/s41380-026-03804-z
Research (Wash D C). 2026 ;9 1367

Maternal Stress Primes Adolescent Stress Susceptibility via Microglial Complement-Dependent Synaptic Phagocytosis.

Xiaoqing Wang, Ming Jiang, Ling Wei, Xinyue Liang, Fang Fang, Yunli Xie, Jing Cang.

Early-life adversity, including prenatal stress exposure, has enduring effects on stress responsivity later in life. Yet the impact of maternal stress on offspring susceptibility to stress and its underlying biological mechanisms remain to be elucidated. Here, we established a "2-hit" stress model to investigate whether maternal chronic unpredictable stress (E9.5 to E18) increases offspring susceptibility to social isolation during adolescence (P28 to P49). Our study reveals that maternal stress increases susceptibility to adolescent social isolation in male-but not female-offspring, manifested as increased anxiety- and depressive-like behaviors. This vulnerability is mediated by the priming of hippocampal dentate gyrus microglia through the complement C3-C3aR signaling pathway, which promotes the aberrant phagocytosis of excitatory synapses and reduces glutamatergic neuronal activity. Notably, pharmacological blockade of C3aR or chemogenetic activation of glutamatergic neurons in the dentate gyrus during adolescence effectively alleviated stress susceptibility. Therefore, our findings identify a targetable immune-mediated mechanism in the hippocampus that underlies stress vulnerability in offspring exposed to gestational maternal stress, offering new avenues for preventing adolescent-onset mood disorders.

DOI: https://doi.org/10.34133/research.1367
Research (Wash D C). 2026 ;9 1384

FKBP5 Orchestrates a Biphasic Microglial Response in Spinal Cord Injury by Sequentially Activating the GPR84/IL-1β Pathway and the LDHA-Lactylation-FXYD5/LGALS1 Axis.

Haotian Li, Jing Wang, Daohui Li, Hangchuan Bi, Jin Yang, Junjie Dong, Zhiqiang Gong, Hongda Gong, Bing Wang, Lingqiang Chen.

Spinal cord injury often causes permanent disability because the body's own repair mechanisms are limited, and the molecules that control damage and healing are not fully understood. One such molecule, FK506-binding protein 5 (FKBP5), is known to rise sharply after injury, but whether it only drives harmful inflammation or also participates in later recovery has been unclear. In this study, we investigated how FKBP5 affects microglia-the brain's immune cells-at different stages after spinal cord injury in mice. We found that FKBP5 plays a dual role. In the first few days, it works together with another protein, GPR84, to boost the production of an inflammatory signal called interleukin-1β. This signal pushes microglia into a destructive state and triggers a coordinated form of neuronal cell death that involves multiple death pathways. However, as FKBP5 levels continue to rise over time, it switches its function. It binds to and modifies an enzyme called LDHA, changing how microglia process lactate. This lactate then acts as a signal to add chemical tags (lactylation) onto histones, which turns on a protective gene, Fxyd5, and its partner Lgals1. These changes convert microglia from a harmful to a healing state, reduce neuronal death, and improve the local environment for tissue repair. Our results reveal that FKBP5 is a double-edged sword-first worsening damage, then promoting repair. This discovery suggests that precisely timing therapies that target FKBP5 could offer a new way to improve recovery after spinal cord injury.

DOI: https://doi.org/10.34133/research.1384
Free Radic Biol Med. 2026 Aug 05. pii: S0891-5849(26)00989-5. [Epub ahead of print]

Microglial SREBP2 regulate cholesterol-related lipid metabolism and inflammatory levels following ischemic stroke via the autophagy pathway.

Wei Wei, Yi Lei, Yongli Pan, Jiacong Tan, Zhongnan Hao, Lin Zhang, Xiaoyue Luo, Meihua Li, Zhipeng Xiao, Wenqiang Xin.

   BACKGROUND: Dysregulated lipid metabolism and inflammation exacerbate brain injury, with abnormal cholesterol metabolism playing a role in stroke condition. SREBPs are key transcription factors regulating lipid synthesis, and their activation is linked to autophagy. It remains unclear whether autophagy clears lipids and modulates inflammation after ischemic stroke, and whether SREBP2 affect cholesterol metabolism and inflammation via autophagy. This study aims to investigate the role of SREBPs and the mediating mechanism of autophagy in post-ischemic stroke lipid dysregulation and inflammation.
METHODS: In vivo mice models of ischemic stroke (middle cerebral artery occlusion, MCAO) and in vitro neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) models were employed. Through interfering with SREBP2, combined with autophagy inhibitor/activator treatment, we detected cholesterol and cholesteryl ester in microglia and brain tissue, the expression levels of inflammatory factors, and the expression changes of autophagy-related proteins (LC3, p62) and SREBP downstream lipid metabolism-related genes.
RESULTS: After ischemic stroke, the expression of SREBP2 in brain tissue was significantly upregulated, the autophagy pathway was activated, accompanied by cholesterol and lipid accumulation and increased expression of inflammatory factors. Interfering with SREBP2 expression significantly inhibited the excessive activation of the autophagy pathway, reduced the content of cholesterol-related lipids in brain tissue and neurons, decreased the release of inflammatory factors, and alleviated cerebral ischemia-reperfusion injury. In microglia-neuron co-culture experiments, SREBPs interference in microglia significantly improved the survival rate of OGD/R-induced injured neurons and reduced neuronal apoptosis, while behavioral tests revealed that SREBP2 interference remarkably promoted neural function recovery in MCAO mice.
CONCLUSION: SREBP2 regulate the autophagy pathway to affect the balance of cholesterol-related lipid metabolism and the intensity of inflammatory responses after ischemic stroke, thereby participating in the pathophysiological process of cerebral ischemic injury, which provides a new target and theoretical basis for the treatment of ischemic stroke.

Keywords:  Ischemic stroke; SREBP2; autophagy; lipid metabolism; microglia; neuroinflammation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.008
Fundam Res. 2026 Jul;6(4): 2235-2249

Multispectral photoacoustic microscopy and NIR-II fluorescence imaging of TREM2-positive microglia in Aβ-driven Alzheimer's pathogenesis.

Hsuan Lo, Shiying Li, Jiali Chen, Qi Zhou, Yang Qiu, Shaoheng Ma, Bo Yu, Tiancheng Gu, Liming Nie.

  Monitoring microglial activation mediators remains challenging in neurodegeneration. Few imaging studies track amyloid-β (Aβ)-linked microglial dynamics across a wide field of view with high spatiotemporal resolution. Leveraging the triggering receptor expressed on myeloid cells 2 (TREM2), a pivotal Alzheimer's disease (AD) biomarker that enhances Aβ clearance while suppressing neuroinflammation, we developed a dual-modal probe, TREM2-ICG, by conjugating a TREM2-specific antibody with indocyanine green (ICG), an FDA-approved dye, for robust in vivo photoacoustic and near-infrared-II (NIR-II) fluorescence imaging. Multi-wavelength photoacoustic microscopy imaged AD pathology at 532 nm (hemoglobin, vasculature), 559 nm (Aβ probe AOI987), and 780 nm (TREM2-ICG for peri‑plaque microglia). Time-resolved NIR-II imaging (30 frames/sec) tracked Aβ-oligomer-induced microglial displacement at ∼50 µm resolution, showing a rapid chemotaxis phenomenon. Immunofluorescence-verified TREM2-microglia plaque engagement demonstrates AD pathogenesis. Overall, our multiscale photoacoustic-fluorescence imaging resolved cortex-wide Aβ-microglial interactions, combining wide-field, high-speed, and deep-penetration to overcome confocal depth and two-photon field of view limits. This enabled in vivo tracking of microglial responses to Aβ, revealing potential for investigating AD-specific mechanisms.

Keywords:  Alzheimer’s disease; Cerebrovascular imaging; Multi-wavelength photoacoustic imaging; NIR-II fluorescence imaging; TREM2-expressed microglia

DOI:  https://doi.org/10.1016/j.fmre.2026.04.016
J Am Heart Assoc. 2026 Aug 07. e048110

Single-Nucleus Transcriptomics Identifies Microglial Interferon Regulatory Factor 5 as a Regulator of Neuroinflammation During Heart Failure Progression After Myocardial Infarction in Rats.

Wanxin Tang, Yang Yu, Jing-Yu Bing, Lei Tong, Robert M Weiss, Shun-Guang Wei.

   BACKGROUND: The paraventricular nucleus (PVN) of the hypothalamus is a key autonomic and cardiovascular regulatory center that contributes to neuroinflammation-driven sympathetic excitation in heart failure. To define the cellular and transcriptional mechanisms underlying inflammatory signaling during heart failure progression, we performed single-nucleus RNA sequencing of the PVN in rats 2 weeks after myocardial infarction (MI).
METHODS: PVN tissues were collected 2 weeks post MI for single-nucleus RNA sequencing analysis. Sequencing data were processed through alignment, dimensionality reduction, clustering, and marker-gene identification to define cell populations and gene expression profiles. Gene Set Variation Analysis and transcriptional regulatory network analyses were performed to identify altered signaling pathways and key transcription factors.
RESULTS: A total of 16 341 nuclei were classified into 5 major cell types: neurons, oligodendrocytes, astrocytes, oligodendrocyte progenitor cells, and microglia. Functional analyses identified microglia as the primary mediators of inflammatory responses in the PVN. Gene Set Variation Analysis revealed substantial pathway alterations across cell types, with microglia exhibiting marked activation of immune-related and cytokine-producing pathways in MI rats. Moreover, IRF5 (interferon regulatory factor 5) was identified as a master transcriptional regulator associated with inflammatory activation and was significantly upregulated in PVN microglia after MI. Increased IRF5 expression in PVN microglia was confirmed by immunofluorescence.
CONCLUSIONS: Single-nucleus RNA sequencing identified distinct cell-specific gene signatures, regulatory networks, and signaling pathways in the PVN during heart failure, with microglial IRF5 emerging as a central regulator of immune activation and inflammatory processes. Activated IRF5 promotes microglial activation and neuroinflammation, thereby enhancing PVN neuronal activity and driving sympathetic and neurohumoral dysregulation in rats with MI. Targeting IRF5 and its downstream pathways may therefore provide new insights into the central inflammatory mechanisms contributing to cardiac dysfunction during heart failure progression.

Keywords:  heart failure; microglia; paraventricular nucleus of hypothalamus; single‐nucleus RNA sequencing; transcriptional regulation

DOI:  https://doi.org/10.1161/JAHA.125.048110
Neurobiol Dis. 2026 Aug 05. pii: S0969-9961(26)00312-8. [Epub ahead of print] 107567

Microglial CX3CR1 signaling mediates synaptic pruning in degenerative cervical myelopathy.

Cindy M Zhou, Azam Asgarihafshejani, James Hong, Sydney T Brockie, Mandana Movahed, Sarah Sadat, Sogolie Kouhzaei, Michael G Fehlings.

  Degenerative cervical myelopathy (DCM) encompasses several conditions that cause compression of the cervical spinal cord. While the pathobiology underlying compression-induced neural degeneration remains incompletely understood, microglial synaptic pruning, driven by CX3CR1, is thought to be a main contributor. The current study builds on previous work demonstrating that Cx3cr1-/- mice exhibit improved gait following DCM and seeks to determine if CX3CR1-mediated synaptic pruning underlies this improvement. We compared C57BL/6 (WT, wild-type) and Cx3cr1-/- mice across 12-weeks of DCM. Locomotor and pain function were assessed using CatWalk and Von Frey outcome measures, respectively. Synaptic and electrophysiological changes were characterized at baseline and after 4-weeks of DCM using pre- and post-synaptic markers, motor evoked potentials (MEPs), and whole-cell patch-clamp recordings. Cx3cr1-/- and WT mice showed differences in locomotion at baseline. Normalization of all groups revealed that Cx3cr1-/- mice exhibited improved locomotion across 12-weeks and greater mechanical sensitivity on Von Frey. 4-weeks post-DCM induction, the microglia of Cx3cr1-/- mice displayed reduced engulfment of excitatory and inhibitory synapses in the dorsal and ventral horns. This was accompanied by a disruption to the dorsal horn excitation-to-inhibition (E/I) balance, driven primarily by a loss of inhibitory transmission as confirmed by whole-cell patch clamp recording, and altered corticospinal-neuromuscular excitability, as confirmed by motor evoked potentials. Together, our findings reveal CX3CR1-mediated microglial synaptic pruning as a potential novel contributor to early DCM pathobiology. Specifically, our results suggest that an absence of pruning shifts the synaptic E/I balance in the dorsal horn, which may underlie the gait benefits observed in Cx3cr1-/- mice.

Keywords:  CX3CR1; Degenerative cervical myelopathy (DCM); Fractalkine signaling; Knockout model; Microglia; Synaptic pruning

DOI:  https://doi.org/10.1016/j.nbd.2026.107567
Neurobiol Dis. 2026 Aug 04. pii: S0969-9961(26)00309-8. [Epub ahead of print]228 107564

Sex-dependent protective effects of microglial tumor necrosis factor on post-stroke inflammation and myelin injury.

Stefano Raffaele, Pernille Vinther Nielsen, Louise Lykke Nielsen, Davide Marangon, Silvia Corradini, Martine Mørck Taagholt, Estrid Thougaard, Ann-Sofie Ellebæk Nyboe Nielsen, Sergei A Nedospasov, Jens D Mikkelsen, Marta Fumagalli, Bettina Hjelm Clausen, Kate Lykke Lambertsen.

  Tumor necrosis factor (TNF) is rapidly induced after ischemic stroke, but its proposed cell-specific and sex-dependent functions during post-stroke inflammation remain insufficiently understood. Here, we investigated the role of microglia-derived TNF in the acute and subacute response to permanent middle cerebral artery occlusion (pMCAO). Tnf expression was transiently upregulated after stroke, becoming significant at 4 h, peaking at 12-24 h, and returning to baseline by 5 days. In situ hybridization confirmed strong Tnf expression in the infarct and peri-infarct regions. Whole-brain transcriptomic profiling showed that global TNF deficiency reshaped the early post-ischemic response, shifting it from microglia-associated phagocytic and wound-healing pathways toward an interferon-related inflammatory signature. To define the specific contribution of microglial TNF, we used inducible Cx3cr1CreER:Tnffl/fl mice. Microglial TNF deletion had no effect on infarct volume in males at 24 h or 5 days after pMCAO, but significantly increased infarct size in females at both time points. In both sexes, brain TNF levels peaked at 24 h and were significantly reduced in Cx3cr1CreER:Tnffl/fl mice, confirming microglia as a major source of early post-ischemic TNF. However, downstream consequences diverged by sex. At 5 days, male Cx3cr1CreER:Tnffl/fl mice showed reduced microglial reactivity and 18 kDa translocator protein (TSPO) signal, with no change in T-cell infiltration, and exhibited increased density of mature oligodendrocytes. In contrast, female Cx3cr1CreER:Tnffl/fl mice displayed enhanced microglial reactivity, increased TSPO binding, higher peri-infarct T-cell infiltration, and reduced oligodendrocyte density and myelin integrity. Together, these findings identify microglial TNF as a sex-dependent regulator of post-stroke inflammation and myelin injury.

Keywords:  Ischemic stroke; Microglia; Myelination; Neuroinflammation; Tumor necrosis factor

DOI:  https://doi.org/10.1016/j.nbd.2026.107564
Glia. 2026 Oct;74(10): e70210

Predicting Relevant Microglia-Associated Cell-Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1.

Janssen M Kotah, Marina Trombetta Lima, Esmée C Dragt, Asimenia Voulgaroglou, Nieske Brouwer, Inge R Holtman, Susanne M Kooistra, Bart J L Eggen.

  Microglia play a key role in the pathophysiology of Alzheimer's Disease (AD) and their increased heterogeneity likely affects disease progression. We previously identified distinct microglial signatures that were enriched in AD donors and associated with amyloid and tau, respectively. Here we generated a snRNAseq dataset from postmortem control and AD cases and analyzed alterations in cell-cell communication pathways that might be relevant to AD pathophysiology. One signaling pathway perturbed in AD cases involved SPP1, and while this pathway was also present in control samples, microglia-microglia SPP1 signaling was restricted to AD donors. Further analyses within microglia-microglia signaling predict AD-specific induction of GAS6-AXL signaling (from inflammatory and ribosomal microglia), and SPP1-ITGAV/ITGB5 signaling (from disease-associated and inflammatory microglia, among others). Together, these findings might in part explain the increased microglia phagocytic profile described in AD. RNAscope confirmed enrichment of SPP1 expressing microglia near amyloid plaques in AD brain tissue samples. These data indicate altered cellular communications between microglia in the AD brain.

Keywords:  Alzheimer's disease; SPP1; cell–cell communication; microglia; single nucleus RNA sequencing

DOI:  https://doi.org/10.1002/glia.70210
Glia. 2026 Oct;74(10): e70209

Gq Signaling in Microglia Triggers Interferon Responses and Improves Outcome After Ischemic Stroke.

Lynn Bitar, Marie-Luise Brehme, Charlotte Oldenburg, Sara Isla Cainzos, Michael G Kaul, Tobias Mummert, Malte Borggrewe, Thomas G Oertner, Tim Magnus.

  Post-stroke recovery remains limited despite advances in acute reperfusion therapies, underscoring the need to better understand underlying mechanisms that shape repair. Microglia, the resident immune cells of the central nervous system, orchestrate responses to ischemic injury and critically influence neurovascular remodeling, axonal reorganization, and functional recovery. Emerging evidence indicates that inflammatory preconditioning can reprogram microglial responses to subsequent insults, yet the exact intracellular signaling pathways mediating this adaptive state remain incompletely defined. Here, we used a chemogenetic approach to selectively activate Gq signaling in microglia employing a microglia-specific DREADD mouse model. This strategy mimics Gq-coupled receptor activation in microglia in the absence of peripheral immune engagement. Pre-ischemic Gq activation significantly reduced infarct sizes at 24 h after experimental stroke in female mice and at 7 days in both sexes. Morphological analyses revealed that Gq-conditioned microglia exhibited increased structural complexity, adopting a highly ramified, spatially compact phenotype and higher CD68 expression, indicating increased phagocytic activity. Transcriptional profiling demonstrated that Gq activation primes autophagy-related defense pathways in microglia, resulting in upregulation of interferon-stimulated genes 7 days after stroke in both sexes. Together, our findings identify Gq signaling as a key modulatory pathway capable of reprogramming microglial phenotype and enhancing stroke recovery. These results highlight the plasticity of microglial signaling networks and support targeted modulation of microglial Gq pathways.

Keywords:  DREADD; interferon‐response; microglia; recovery phase; stroke

DOI:  https://doi.org/10.1002/glia.70209
Mol Neurobiol. 2026 Aug 05. pii: 810. [Epub ahead of print]63(1):

GPR146 Deficiency Enhances Microglial Phagocytosis and Blood-Brain Barrier-Associated Markers in an Acute Amyloid-β Model.

Shaobin Yang, Yanhong Li, Yanling Guo, Yumeng Li, Meiqi Li, Hongxia Li, Yimeng Zhang.

  Dysregulation of brain cholesterol homeostasis is increasingly recognized as a critical driver of Alzheimer's disease (AD) pathogenesis. G protein-coupled receptor 146 (GPR146) has emerged as a pivotal regulator of systemic cholesterol metabolism; however, its role in the central nervous system and AD remains elusive. Here, we report that GPR146 deficiency in mice modulates ERK/PKA signaling without affecting baseline physiology or general behavior. Following intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)42 oligomers, GPR146 was associated with altered Aβ42-evoked ERK/PKA/Akt signaling both in vivo and in vitro. Mechanistically, Gpr146 ablation potentiated microglial Aβ phagocytosis, which correlated with the transcriptional upregulation of phagocytic receptors, including TREM2, GPR34, P2Y6, and CR3, alongside increased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Moreover, GPR146 deficiency was linked to elevated levels of blood-brain barrier (BBB)-associated markers Cldn-5 and Glut-1 protein levels, while attenuating Aβ‑induced inflammatory responses in brain endothelial cells. At the metabolic level, GPR146 knockout modulated the expression of key enzymes governing glucose (GLUT1, GLUT3, G6PD, PFK, HK) and lipid (HMGCS1, ACACA, FASN, SCD1) metabolism and markedly reduced Aβ‑elicited lipid droplet accumulation in the cortex and hippocampus. Collectively, our findings establish GPR146 as a novel neurometabolic regulator whose deficiency correlates with enhanced Aβ phagocytosis, maintenance of BBB-associated proteins, and altered cerebral metabolism, thereby presenting a potential therapeutic axis for early AD intervention.

Keywords:  Alzheimer’s disease; Amyloid-beta; Blood–brain barrier; G protein–coupled receptor 146; Metabolism

DOI:  https://doi.org/10.1007/s12035-026-06100-7
Genomics. 2026 Aug 04. pii: S0888-7543(26)00108-4. [Epub ahead of print]118(5): 111300

Single-cell analysis of the human retina reveals stage-linked microglial states and neural-immune circuit rewiring in diabetic retinopathy.

Luning Yang, Sen Lin, Yiwen Tao, Qi Pan, Tengda Cai, Yunyan Ye, Jianhui Liu, Yang Zhou, Quanyong Yi, Zen Huat Lu, Lie Chen, Gareth McKay, Richard Rankin, Yongqing Shao, Weihua Meng.

  Diabetic retinopathy (DR) is a major cause of vision loss worldwide. Here, we conduct single-cell RNA sequencing of twenty human retina samples (from living and post-mortem donors) across non-diabetic, diabetic, and DR states to create a comprehensive transcriptomic atlas. We identify two stable microglial populations-homeostatic and inflammatory-that exist along a functional continuum, plus a neutrophil cluster within C1QA+ myeloid cells with dynamic transitions occurring throughout disease progression. Module-level analysis reveals divergent transcriptional trajectories: homeostatic microglia maintain energetic programs while selectively upregulating stress elements, whereas inflammatory microglia layer additional pro-inflammatory programs onto preserved biosynthetic foundations. Eleven co-expression modules organize into two major axes: an inflammatory-stress axis, and a regulatory/metabolic-motility axis, with a stable translation module persisting across disease stages. Cell communication analysis further highlights sophisticated neural-immune interactions, particularly between photoreceptors and microglia. Our findings provide insights into the complex cellular dynamics of DR progression and suggest potential therapeutic targets for early intervention.

Keywords:  Diabetes; Diabetic retinopathy; Human retina; Microglial states; Neural-immune interactions; Single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.ygeno.2026.111300