bims-microg 2026-05-03 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–05–03
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Kif15 Orchestrates Neuronal-Microglial Communication via CX3CL1 to Impede Nerve Regeneration.
NSUN5 Deficiency Drives Anxiety-Like Behaviors in Mice via Increased Microglial Activation and Impaired LTD Induction in the Basolateral Amygdala.
Galectins as stress-integrating regulators of neuroimmune signaling and proteinopathy in the central nervous system.
Genetic correlation analysis of Alzheimer's disease and stroke implicates PHLPP1 as a shared locus in individuals of African ancestry.
A Long-Lived Human Neurovascular PENTA Culture Model Captures Incomplete Vascular Repair and Glia-Associated Signaling After Traumatic Brain Injury.
SGK1 inhibition supports neuroprotection in spinal cord injury by suppressing oxidative stress and AIM2 activation via FoxO1 mediated mitophagy.
Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics.
Characterizing the metabolomes of microglia, astrocytes and neurons in ageing and Alzheimer's brains.
Serum albumin-fused interleukin-10 prevents neuroinflammation by promoting immunoregulation in the secondary lymphoid organs and limiting immune cell infiltration in the spinal cord.
Niacin promotes motor function recovery after spinal cord injury via Hcar2-dependent microglia immunometabolic regulation.
Complement C3aR deletion does not attenuate degeneration in a tauopathy model or alter acute inflammation-induced gene expression changes.
Transcranial photobiomodulation mitigates neuroinflammation by suppressing the activation of neurotoxic microglia through inhibition of the cGAS-STING pathway following intracerebral hemorrhage in mice.
Aldose reductase inhibition suppresses microglial endoplasmic reticulum stress and ferritinophagy in ischemic stroke.
The mechanism of different microglial receptors mediating central inflammation in chronic migraine: a meta-analysis.
Lactate modulates microglial M2 polarization via H3K9 lactylation in ischemic stroke.
A microglia membrane biomimetic platinum-based MOF-loaded quercetin nanodrug delivery system for the treatment of Alzheimer's disease.
Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies.
SCD2 Alleviates Diabetes-Associated Cognitive Dysfunction by Improving Microglial Lipid Metabolism.
Perivascular SPP1 Drives Microglial Synaptic Engulfment After Ischemic Stroke.
Dual-peptide engineered macrophage membrane biomimetic nanosystem via targeting Rg1 delivery for traumatic brain injury therapy.

J Biol Chem. 2026 Apr 27. pii: S0021-9258(26)01962-9. [Epub ahead of print] 113090

Kif15 Orchestrates Neuronal-Microglial Communication via CX3CL1 to Impede Nerve Regeneration.

Ronghua Wu, Wei Zhang, Xiaowei Qian, Zhangji Dong, Xiaomei He, Siming Zhang, Taoran Chen, Liu Yang, Yan Liu, Mei Liu.

  Kinesins, a class of microtubule (MT)-dependent molecular motors, regulate MT dynamics and MT-mediated transport. We previously identified Kif15 (kinesin-12) as a key player in axonal growth by modulating MT remodeling during neuronal development, and more recently, its involvement in protein localization. In this study, we observed that Kif15 knockout (Kif15 KO) mice exhibited accelerated functional recovery after sciatic nerve injury. To investigate the cellular responses underlying this enhanced recovery after axotomy, spinal cord tissues from the injured regions were collected for single-nucleus RNA sequencing (snRNA-seq). The snRNA-seq results revealed differential genes expression in neurons, indicating a neuroprotective shift in Kif15 KO mice, and in microglia, where a repair-promoting and synapse-modulating profile was observed. Notably, the CX3CL1-CX3CR1 signaling pathway, critical for neuronal-microglial communication, was downregulated in Kif15 KO mice compared to wild-type controls. Further molecular analysis indicated that Kif15 facilitated the expression and localization of neuronal CX3CL1, which, in turn, influenced microglial function via the receptor CX3CR1. Our findings highlight a novel role for Kif15 in regulating neuronal-microglial communication through modulation of CX3CL1 signaling.

Keywords:  CX3CL1-CX3CR1; Kif15; neuronal-microglial communication; sciatic nerve injury; snRNA-seq

DOI:  https://doi.org/10.1016/j.jbc.2026.113090
FASEB J. 2026 May 15. 40(9): e71863

NSUN5 Deficiency Drives Anxiety-Like Behaviors in Mice via Increased Microglial Activation and Impaired LTD Induction in the Basolateral Amygdala.

Kailing He, Zhaochun Shi, Zimei Huang, Peipei Chen, Xinwen Chen, Qingxian Xu, Wenyi Jiang, Zihao Yuan, Sha Sha, Ling Chen, Tingting Zhang.

  Williams-Beuren Syndrome (WBS), is a neurodevelopmental disorder characterized by anxiety, hypersociality and neurocognitive abnormalities, resulting from a heterozygous microdeletion on chromosome 7q11.23. A cytosine-5 RNA methyltransferase, NSUN5, is one of the deleted genes, which has been linked to cognitive deficits in WBS patients. However, the relation of NSUN5 to anxiety disorders and underlying mechanisms remain unknown. Here, we report that NSUN5 deficiency triggers anxiety-like behaviors without hypersociality in both adult male and female mice. NSUN5 exhibits specific expression in oligodendrocyte precursor cells (OPCs) within the basolateral amygdala (BLA), which is one of the main brain regions linked to anxiety. In addition, NSUN5 deficiency in mice leads to reduced OPCs proliferation accompanied with microglial activation. Mechanistically, we revealed that the specific decline in secretion of OPCs-derived fibroblast growth factor 2 (FGF2) resulted in microglial activation and exacerbated the levels of TNFα and IL-1β cytokines in NSUN5-deficient mice. Field excitatory postsynaptic potentials (fEPSPs) slopes at external capsule BLA synapse were increased in NSUN5-deficient mice. Moreover, an increase in paired-pulse inhibition and an impairment of long-term depression (LTD) induction were observed in NSUN5-deficient mice, which could be rescued either by intra-BLA injection of recombinant mouse FGF2 (rmFGF2) or by pharmacological suppression of microglial activation with minocycline. Furthermore, the anxiety-like behaviors in NSUN5-deficient mice were also relieved by rmFGF2 or minocycline treatments. Taken together, our study unveils a previously unknown effect of NSUN5 on anxiety disorders and a role of NSUN5 in regulating OPCs-microglia interaction and synaptic plasticity of BLA.

Keywords:  NSUN5; anxiety; basolateral amygdala; oligodendrocyte precursor cells; synaptic plasticity

DOI:  https://doi.org/10.1096/fj.202600754R
Neurobiol Dis. 2026 Apr 24. pii: S0969-9961(26)00155-5. [Epub ahead of print]224 107410

Galectins as stress-integrating regulators of neuroimmune signaling and proteinopathy in the central nervous system.

Jian Jing Siew, Yijuang Chern.

  Galectins are β-galactoside-binding lectins that play increasingly mechanistic functions in central nervous system (CNS) physiology and disease. Over the past decade, a rapidly expanding literature has identified galectins as regulators of microglial activation, misfolded protein pathology, vesicle damage sensing, autophagy, synaptic plasticity, myelination, vascular repair, and neuroimmune communication. Galectins operate across intracellular and extracellular compartments to integrate cellular stress and innate immune signaling. Here, we review CNS studies of galectin-1, galectin-3, galectin-4, galectin-8, and galectin-9, focusing primarily on work published from 2019 onward while incorporating selected earlier studies to establish foundational concepts. Across experimental models and human studies, galectins orchestrate microglial state transitions, regulate aggregation and propagation of amyloid-β, tau, α-synuclein, and mutant huntingtin, and function as intracellular sensors of vesicle and lysosomal damage. Multiple studies further establish galectins as biomarkers and therapeutic targets across Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, retinal degeneration, and chronic pain. Importantly, this review highlights a stage- and context-dependent paradox in which the same galectin axis can amplify neuroinflammation and proteopathic spread in some settings yet support recovery or tissue protection in others. Together, these findings position galectins as central regulators that convert intracellular stress into coordinated neuroimmune programs shaping proteinopathy, circuit dysfunction, and tissue remodeling.

Keywords:  Galectin; Microglia; Neurodegeneration; Proteinopathies

DOI:  https://doi.org/10.1016/j.nbd.2026.107410
Alzheimers Dement. 2026 Apr;22(4): e71433

Genetic correlation analysis of Alzheimer's disease and stroke implicates PHLPP1 as a shared locus in individuals of African ancestry.

ADGC, AfDC

   INTRODUCTION: Neuropathological studies indicate a strong association between Alzheimer's disease (AD) and stroke, yet the molecular mechanisms underlying this association remain unclear.
METHODS: Local genetic correlation analysis was conducted with LAVA (Local Analysis of [co]Variant Annotation) using the results from genome-wide association studies on AD and stroke in individuals of African ancestry. Enhanced Hi-C Capture Analysis (eHiCA) examined chromatin interactions using induced pluripotent stem cell (iPSC) -derived cells from AD brain autopsy samples.
RESULTS: LAVA identified a region shared between AD and stroke on chromosome 18q21.33(rg = 0.77, p = 2.41×10-6). eHiCA demonstrated that the AD and stroke loci interact with regulatory elements in PHLPP1. Variants at PHLPP1 were also associated with AD in an independent set of individuals of African ancestry (p = 4.56 × 10-5).
DISCUSSION: This study identified a region on top of PHLPP1 as a locus associated with both AD and stroke. PHLPP1 inhibits protein kinase B, which contributes to both AD and stroke pathophysiology.

Keywords:  Alzheimer's disease; genetic covariance; stroke

DOI:  https://doi.org/10.1002/alz.71433
Adv Healthc Mater. 2026 Apr 29. e04884

A Long-Lived Human Neurovascular PENTA Culture Model Captures Incomplete Vascular Repair and Glia-Associated Signaling After Traumatic Brain Injury.

Daniel S Hinrichsen, Sunghyun Jun, Colleen M Arrasmith, Charitha C Anamala, Mitchell D Thielen, Anapaula Garcia, Volha Liaudanskaya.

  Traumatic brain injury (TBI) frequently leads to chronic neurovascular dysfunction, yet mechanistic insights into human-specific responses have been limited by the absence of long-term, multicellular in vitro models. Here, we report a five-cell-type human neurovascular culture system, comprising endothelial cells, astrocytes, pericytes, microglia, and neurons, engineered within a 3D scaffold to study injury-induced remodeling over multiple weeks. This PENTA-culture platform captures key structural and molecular features of the neurovascular unit and supports compartment-resolved profiling of vascular and neuroimmune responses. Under baseline conditions, PENTA cultures exhibit restricted tracer distribution relative to simpler culture configurations, consistent with the emergence of barrier-like properties within the 3D scaffold. Following mechanical trauma, cultures exhibit a biphasic response characterized by acute endothelial disorganization, mitochondrial structural changes, and neuroimmune alterations, followed by delayed and incomplete structural recovery, accompanied by shifts in angiogenic and immunomodulatory signaling consistent with Tyrosine kinase with immunoglobulin-like epidermal growth factor-like domains 2 (Tie2)- and Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT)-associated signatures. At last, the inclusion of microglia and neurons is associated with improved cytokine resolution and partial recovery of junctional organization, highlighting the influence of neuroimmune complexity on post-injury vascular remodeling. Together, this long-lived, human-derived platform provides a structurally complex and functionally informative system for characterizing neurovascular injury signatures following TBI.

Keywords:  neurovascular unit; traumatic brain injury; vascularized 3D brain model

DOI:  https://doi.org/10.1002/adhm.202504884
J Neuroinflammation. 2026 May 02.

SGK1 inhibition supports neuroprotection in spinal cord injury by suppressing oxidative stress and AIM2 activation via FoxO1 mediated mitophagy.

Yige Chen, Yikang Wang, Nongtao Fang, Jiawei Xu, Yiwei Teng, Ke Wang, Longze Huang, Haifen Ni, Yongli Wang, Kailiang Zhou, Yan Lin, Yao Li.

  Spinal cord injury (SCI) is accompanied by a significant microglia-associated inflammatory response that is associated with secondary tissue damage and poorer functional outcomes. Serum and glucocorticoid-regulated kinase 1 (SGK1) has been implicated in the regulation of cell survival and neuronal excitability in various diseases. However, the role and cell-specific mechanism of SGK1 in SCI remain to be elucidated. In this study, we observed that SGK1 was predominantly expressed in microglia located at the lesion margin during the early phase of SCI in a mouse contusion model. Inhibition of SGK1 by GSK650394 has been shown to promote neural repair while simultaneously suppressing neuroinflammation and mitochondrial oxidative stress. Mechanistically, the inhibition of SGK1 results in a reduction of FoxO1 phosphorylation and the promotion of nuclear import, consequently inducing microglial mitophagy and promoting mitochondrial homeostasis, leading to the suppression of absent in melanoma 2 (AIM2) related pyroptosis and the conversion of microglia into a neuroprotective M2 phenotype. In particular, AIM2 overexpression or deletion effectively interfered with the influence of SGK1-FoxO1 on the modulation of SCI. In conclusion, the present findings provide a potential therapeutic strategy for the treatment of SCI.

Keywords:  Absent in melanoma 2; Inflammasome; Mitochondria; Serum and glucocorticoid-regulated kinase 1; Spinal cord injury

DOI:  https://doi.org/10.1186/s12974-026-03844-w
J Neuroinflammation. 2026 Apr 25.

Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics.

Clair C Ashley, Nicholas J Constantino, Ryan J Pettit-Mee, J Andy Snipes, Kai Saito, Riley E Irmen, Rui Zhang, Evan M Neary, Matthew J Lanning, Celeste M Karch, Lance A Johnson, Josh M Morganti, Shannon L Macauley.



Keywords:  Amyloid plaques; Lactate; Metabolism; Microglia

DOI:  https://doi.org/10.1186/s12974-026-03825-z
Nat Cell Biol. 2026 Apr 30.

Characterizing the metabolomes of microglia, astrocytes and neurons in ageing and Alzheimer's brains.

Jie Yu, Fengzhi Li, Xing-Jun Chen, Chenye Mou, Di Yao, Zhanying Bi, Xiaoli Chen, Lulu Du, Ziyan Feng, Xinshuang Zhang, Xiaoqian Yu, Lauren G Zacharias, Ralph J DeBerardinis, Li Zhang, Zhen Li, Benyan Luo, Xiao-Ling Hu, Woo-Ping Ge.

Neurons and glia are distinct in their morphology, development and function, possessing unique transcriptomes and proteomes, but little is known about their metabolomes. The challenge of brain cell metabolic profiling is to obtain a large number of cells for reliable analysis. Here we purified microglia, astrocytes and neurons from mouse brains, identifying >70 metabolites through targeted metabolomics and 9,854 metabolite features via untargeted metabolomics. We systematically characterized cell type-enriched metabolites and metabolic pathways, revealing an enrichment of glutathione (GSH) and polyamine metabolism in microglia. This enrichment was validated in vivo and showed significant decreases with ageing and in an Alzheimer's disease model. Notably, GSH and polyamine metabolism correlated strongly with chemokine-related gene expression. Disrupting the GSH pathway in microglia resulted in downregulation of chemokine-related genes, aberrant morphogenesis and β-amyloid deposition. Our results provide a valuable resource ( https://metabolismocean.org/braincell ) for metabolic studies related to ageing, Alzheimer's disease and other neurological diseases.

DOI: https://doi.org/10.1038/s41556-026-01910-2
bioRxiv. 2026 Apr 14. pii: 2026.04.10.717764. [Epub ahead of print]

Serum albumin-fused interleukin-10 prevents neuroinflammation by promoting immunoregulation in the secondary lymphoid organs and limiting immune cell infiltration in the spinal cord.

Erica Budina, Joseph W Reda, Kirsten C Refvik, Julia Luehr, Brendan T Berg, Hye-Rin Chun, Taryn N Beckman, Ani Solanki, Mindy Nguyen, Sofia N Reda, Colleen R Foley, Ivan Vuong, Abigail L Lauterbach, Kevin Hultgren, Suzana Gomes, Jun Ishihara, Lisa R Volpatti, Jeffrey A Hubbell.

Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that suppresses pro-inflammatory cytokine production, reduces antigen presentation by myeloid cells, promotes M2 macrophage polarization, and inhibits T cell activation. Despite these well-established immunoregulatory functions, efforts to harness recombinant IL-10 therapeutically have been limited by its short plasma half-life and poor retention in the secondary lymphoid organs (SLOs), key sites of autoreactive T cell priming in autoimmune disease. Previously, we engineered a fusion of serum albumin and IL-10 (SA-IL-10) with extended half-life and enhanced exposure in the SLOs following intravenous administration. Here, we integrate human transcriptomic analyses and a murine model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE), to investigate how sustained IL-10 exposure in the SLOs modulates immune responses under inflammatory conditions. Human single-cell RNA sequencing analyses revealed reduced IL-10 expression alongside increased IL-10 receptor expression across multiple immune cell populations in treatment-naïve patients with multiple sclerosis (MS), motivating the investigation of IL-10-based immunomodulatory strategies. Prophylactic SA-IL-10 administration prevented the development and progression of EAE with superior efficacy to wild type IL-10 and comparable protection to fingolimod, an FDA-approved MS therapy. Immunophenotyping of the SLOs revealed that SA-IL-10 suppressed pathogenic, antigen-specific RORγt + Foxp3 - T H 17 T cells, CD86 + M1-like macrophages, CD86 + dendritic cells, and pro-inflammatory cytokine production, while expanding immunoregulatory CD206 + M2-like macrophages and increasing the frequency of multiple checkpoint markers (CTLA-4, PD-1, TIGIT, ICOS) on GATA3 + Foxp3 - T H 2 cells. Despite the absence of direct central nervous system targeting, SA-IL-10 treatment also reduced the infiltration of macrophages, dendritic cells, and CD4 + T cells into the spinal cord. Repeated SA-IL-10 administration was well tolerated, as treated EAE mice gained significantly more body weight over the course of treatment compared to PBS- and WT IL-10-treated controls, and exhibited plasma biochemistry parameters comparable to control animals at study endpoint. Together, these findings demonstrate that increasing IL-10 exposure in the SLOs suppresses neuroinflammation by promoting immunoregulation.
One Sentence Summary: Subcutaneously administered serum albumin-fused interleukin-10 prevents experimental autoimmune encephalomyelitis by suppressing pathogenic T H 17 cells and pro-inflammatory myeloid cells in the secondary lymphoid organs and spinal cord, while expanding immunoregulatory cells in the secondary lymphoid organs.

DOI: https://doi.org/10.64898/2026.04.10.717764
Clin Transl Med. 2026 May;16(5): e70683

Niacin promotes motor function recovery after spinal cord injury via Hcar2-dependent microglia immunometabolic regulation.

Hua Du, Lingnian Zeng, Chan Liu, Huyao Zhou, Xia Wang, Qing Ai, Jinpiao Zhu, Nong Xiao.

   BACKGROUND: Traumatic spinal cord injury (SCI) induces a robust local inflammatory response that can both facilitate repair and exacerbate pathology. Hydroxycarboxylic acid receptor 2 (Hcar2) is known to exert immunomodulatory effects; however, its role in SCI and its potential for targeting Hcar2 to alleviate motor deficits remain unclear.
METHODS: The spinal cord transcriptome following SCI, with a focus on Hcar2, was analysed via publicly available single-cell RNA sequencing datasets from mice and rhesus macaques. Additionally, an in vivo SCI mouse model with Hcar2 knockout and an in vitro LPS-induced BV2 microglial model were established to assess Hcar2 gene and protein expression, microglial activation and inflammatory responses via bulk RNA sequencing, immunofluorescence staining, Western blotting, and real-time polymerase chain reaction. To evaluate the protective effects of Hcar2 activation, niacin, a known Hcar2 agonist, was administered to mice or BV2 cells, followed by assessments of the inflammatory response and motor function.
RESULTS: Hcar2 gene expression, which was enriched predominantly in spinal cord microglia, was upregulated following SCl, peaking at 7 days post-SCl. Genetic knockout of Hcar2 decreased the percentage of impaired anti-inflammatory polarized microglia and increased the inflammatory response. In contrast, Hcar2 activation with niacin in LPS-stimulated microglia BV cell models reversed mitochondrial dysfunction, increased the oxygen consumption rate and reduced the expression of the cytokines IL-6 and IL-1β. The administration of niacin to SCl mice upregulated anti-inflammatory microglia, reduced the expression of multiple proinflammatory cytokines, increased the number of motor neurons and improved motor function recovery. Notably, all these protective effects were abolished by genetic loss of Hcar2.
CONCLUSIONS: Hcar2 serves as a critical regulator of microglial polarization, promoting the switch from a proinflammatory phenotype to an anti-inflammatory phenotype through immunometabolic reprogramming. Targeting Hcar2 with niacin may offer a translatable therapeutic strategy to improve functional recovery after SCl.
KEY POINTS: Hcar2 is identified as a conserved, injury-induced metabolic checkpoint specifically enriched in microglia following spinal cord injury. Hcar2 activation reprogrammes microglial metabolism from glycolysis to oxidative phosphorylation to drive reparative anti-inflammatory polarization. Pharmacological targeting of Hcar2 with niacin resolves neuroinflammation and promotes functional motor recovery in an Hcar2-dependent manner.

Keywords:  hydroxycarboxylic acid receptor 2; immunometabolism; metabolic reprogramming; microglia; neuroinflammation; niacin; spinal cord injury

DOI:  https://doi.org/10.1002/ctm2.70683
Cell Rep. 2026 Apr 24. pii: S2211-1247(26)00391-8. [Epub ahead of print]45(5): 117313

Complement C3aR deletion does not attenuate degeneration in a tauopathy model or alter acute inflammation-induced gene expression changes.

Yuanyuan Wang, Shristi Pandey, Martin Weber, Man Kin Choy, Tiffany Wu, Tania Chernov-Rogan, Max Adrian, Ming-Chi Tsai, Hai Ngu, Oded Foreman, Luke Xie, Jesse E Hanson.

  Aberrant activation of the classical complement pathway in the brain is implicated in contributing to synapse loss and neurodegeneration in various neurodegenerative conditions. Given that C3aR is a druggable target in the complement pathway, we evaluated the potential of C3aR knockout (KO) to rescue neurodegeneration in a tauopathy model and neuroinflammatory responses in an acute endotoxemia model. We found that C3aR KO did not rescue Tau pathology, microglia activation markers, neurodegeneration, or behavioral abnormalities in tauopathy model mice. While we found that endotoxemia resulted in numerous transcriptional changes, including distinct alterations in subpopulations of microglia, astrocytes, and oligodendrocytes, C3aR KO did not impact these alterations. Together, our results suggest that the beneficial effects of blocking the complement classical pathway in neurodegeneration models are likely independent of C3aR activation and raise questions about the rationale for therapeutically targeting C3aR for neurodegenerative disease.

Keywords:  Alzheimer’s disease; C3aR; CP: neuroscience; complement; microglia; neurodegeneration; neuroinflammation; single-cell RNA-seq; tauopathy

DOI:  https://doi.org/10.1016/j.celrep.2026.117313
Chin Med J (Engl). 2026 Apr 27.

Transcranial photobiomodulation mitigates neuroinflammation by suppressing the activation of neurotoxic microglia through inhibition of the cGAS-STING pathway following intracerebral hemorrhage in mice.

Yitong Du, Song Wang, Yuhualei Pan, Huixuan Ma, Yushang Zhao, Zheng Wei, Huadong Lu, Dan Xie, Yongbo Zhang.

   BACKGROUND: Neuroinflammation driven by microglial activation is a key contributor to secondary brain injury after intracerebral hemorrhage (ICH). This study aimed to determine whether transcranial photobiomodulation (tPBM) modulates microglial activation and improves neurological outcomes following ICH.
METHODS: In this study, we used a mouse model of ICH induced by collagenase to investigate the effects of tPBM at three different power levels (25, 50, and 100 mW) on neurological function, hematoma volume, brain edema, and blood-brain barrier (BBB) integrity. We conducted neurobehavioral assessments and analyzed the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway through quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. In addition, we used the STING-specific inhibitor H151 and agonist diABZI to elucidate the role of the cGAS-STING pathway in neuroinflammation.
RESULTS: tPBM treatment significantly improved neurological recovery, with optimal effects observed at 50 mW. This treatment reduced hematoma volume, alleviated brain edema, and preserved BBB integrity. Importantly, tPBM inhibited microglial polarization toward a neurotoxic phenotype by suppressing the activation of the cGAS-STING pathway. The use of H151 resulted in decreased neuronal apoptosis and inflammatory cytokine expression, whereas diABZI reinstated inflammatory processes, highlighting the detrimental role of cGAS-STING overactivation in ICH.
CONCLUSIONS: tPBM effectively mitigates neuroinflammation and enhances functional recovery after ICH by modulating the cGAS-STING signaling pathway and suppressing neurotoxic microglial activation. This study underscores the potential of tPBM as a novel therapeutic intervention for improving outcomes in patients with ICH, warranting further exploration in clinical settings.

Keywords:  Blood–brain barrier; Intracerebral hemorrhage; Microglia; Neutrophil; Transcranial photobiomodulation; cGAS-STING

DOI:  https://doi.org/10.1097/CM9.0000000000004019
Acta Pharmacol Sin. 2026 Apr 27.

Aldose reductase inhibition suppresses microglial endoplasmic reticulum stress and ferritinophagy in ischemic stroke.

Xing-Xing Tu, Fu-Lan Luo, Ting-Wei Deng, Jia-Hui Li, Jia-Kang Wang, Jiang-Ping Xu, Hai-Tao Wang.

  Aldose reductase (AR) is involved in the pathogenesis of ischemic stroke; however, the mechanisms are not well understood. This study aimed to evaluate the role and underlying mechanisms of AR inhibition in ischemic stroke. We found that microglial neuroinflammatory responses to oxygen glucose deprivation/reperfusion (OGD/R) were attenuated by either sorbinil-mediated AR inhibition or AR knockdown. Sorbinil (5-20 μM) attenuated OGD/R-induced endoplasmic reticulum (ER) stress and downstream c-Jun N-terminal kinase (JNK) activation in microglia. Further analysis revealed that sorbinil suppressed microglial autophagic hyperactivation, reduced nuclear receptor coactivator 4 expression, and elevated ferritin heavy chain (FTH1) levels. This effect was accompanied by diminished FTH1 colocalization with lysosomes and decreased intracellular iron (Fe2+) concentrations. Critically, FTH1 knockdown attenuated the inhibitory effect of sorbinil on Fe2+ and interlenkin-1β in microglia. Furthermore, sorbinil mitigated OGD/R-triggered oxidative stress in microglia. Moreover, sorbinil had similar effects on microglia exposed to thapsigargin-induced ER stress. Notably, the protective efficacy of sorbinil was attenuated by the pharmacological activation of JNK. In a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model, sorbinil (4, 8, and 16 mg/kg; i.p.) ameliorated neurological deficits and decreased the volume of cerebral infraction in MCAO/R model mice. This suppression coincided with attenuated neuroinflammation and the activation of ER stress and ferritinophagy in MCAO/R model mice. Overall, this study reveals a novel role of AR inhibition in regulating microglial ER stress-ferritinophagy signaling during cerebral ischemia. AR represents a promising therapeutic target for mitigating cerebral ischemia‒reperfusion injury.

Keywords:  ER stress; aldose reductase; ferritinophagy; ischemic stroke; neuroinflammation

DOI:  https://doi.org/10.1038/s41401-026-01796-8
J Headache Pain. 2026 Apr 27. pii: 122. [Epub ahead of print]27(1):

The mechanism of different microglial receptors mediating central inflammation in chronic migraine: a meta-analysis.

Xinyu Lin, Wenjing Yu, Jiafei Lou, Zhijian Cao, Wenwen Song.



Keywords:  Hyperalgesia; Inflammation; Microglia; Migraine

DOI:  https://doi.org/10.1186/s10194-026-02372-5
J Transl Int Med. 2026 Apr;14(2): 276-293

Lactate modulates microglial M2 polarization via H3K9 lactylation in ischemic stroke.

Bingwei Li, Kan Xu, Jinlu Yu.

   Background and Objectives: Ischemic stroke triggers pathological neuroinflammation primarily mediated by microglial activation. However, the epigenetic impact of lactate, a metabolite that accumulates during cerebral ischemia, on this process has not been comprehensively investigated. This study aimed to determine whether lactate influences microglial polarization through histone lactylation during prolonged cerebral ischemia.
Methods: In vitro models using lactate-treated BV-2 microglia and in vivo models of transient middle cerebral artery occlusion (MCAO) mice were established. Analyses were conducted at 4 to 12 h post-occlusion. Our comprehensive analysis included H3K9la-targeted CUT& Tag sequencing, Nrf2 promoter-specific ChIP-qPCR, flow cytometry for polarization markers, cytokine enzyme-linked immunosorbent assays (ELISAs), and neuronal viability assays.
Results: Under ischemic conditions, lactate markedly increased H3K9 lactylation, with selective enrichment at Nrf2 promoters. This epigenetic modification resulted in a phenotypic shift toward anti-inflammatory M2 states in microglia, both in vitro and in vivo. Mechanistically, H3K9la activated the Nrf2/HO-1 pathway, effectively suppressing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and significantly reducing pro-inflammatory cytokine secretion. Importantly, conditioned medium derived from lactate-treated microglia mitigated the neurotoxic efects induced by microglia to some extent.
Conclusion: Our findings suggest that lactate confers neuroprotection via epigenetic activation of Nrf2 via H3K9la, thereby polarizing microglia towards inflammation-resolving states. This finding uncovers a novel metabolic-epigenetic target for therapeutic intervention in ischemic stroke.

Keywords:  Nrf2; histone lactylation; ischemic stroke; microglial polarization; neuroprotection

DOI:  https://doi.org/10.1515/jtim-2026-0010
J Mater Chem B. 2026 Apr 28.

A microglia membrane biomimetic platinum-based MOF-loaded quercetin nanodrug delivery system for the treatment of Alzheimer's disease.

Ruixin Zhao, Mengrong Guo, Fengmei Yang, Yujiao Yan, Die Tian, Liran Deng, Qi Wang, Meng Xie.

The aberrant deposition of β-amyloid (Aβ) is a central pathological hallmark of Alzheimer's disease (AD), triggering oxidative stress, metal ion dyshomeostasis, and excessive microglial activation in a self-perpetuating pathological cascade. To address these interconnected processes, a platinum-based metal-organic framework (Pt-MOF) with intrinsic antioxidant enzyme-mimetic activity was constructed and loaded with quercetin (Qu) to regulate microglial dysfunction. To enhance blood-brain barrier (BBB) penetration and inflammation-targeting capability, Pt-MOF/Qu was further camouflaged with microglial cell membranes (BV2), yielding Pt-MOF/Qu/BV2 nanoparticles. In vitro studies demonstrated that Pt-MOF/Qu/BV2 efficiently scavenged reactive oxygen species and effectively chelated Cu2+ ions via surface functional groups, thereby inhibiting Aβ aggregation and promoting the disassembly of preformed Aβ aggregates. In addition, the Pt-MOF enabled efficient loading and controlled release of Qu, which significantly restored mitochondrial membrane potential and alleviated microglial over-activation. The BV2 membrane coating markedly improved the biocompatibility and BBB translocation efficiency of the nanoplatform. Furthermore, Pt-MOF/Qu/BV2 significantly reduced reactive oxygen species (ROS) in vivo and Aβ brain plaque accumulation in the head region, alleviated neurotoxicity and improved the behavioral phenotype in the C. elegans AD model. Overall, this biomimetic multifunctional MOF-based nanoplatform represents a promising multi-target therapeutic strategy for AD.

DOI: https://doi.org/10.1039/d6tb00201c
Cells. 2026 Apr 15. pii: 699. [Epub ahead of print]15(8):

Astro-Versus Microglia-Enriched Transcriptomes from Aged Atxn2-CAG100-Knockin Mice Suggest Underlying Pathology of RNA Processing at Ribosomes, and Possibly at U-Bodies.

Georg Auburger, Arvind Reddy Kandi, Rajkumar Vutukuri, Luis-Enrique Almaguer-Mederos, Suzana Gispert, Nesli-Ece Sen, Jana Key.

  Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis type 13 (ALS13) are triggered by polyglutamine expansion in Ataxin-2 (ATXN2). To understand these neurodegenerative disorders at the molecular level, the brains of 10-month-old Atxn2-CAG100-knockin mice were analyzed as microglial, astroglial and neuronal fractions via global RNA sequencing. Data were validated by comparison with the spinal cord oligonucleotide microarray profile or filtered by RNA-seq consistency. Here, we show that the mutation causes a massive inflammatory response in microglia and a reciprocal loss of neuronal transcripts in glial fractions, suggesting severe synapse loss. Beyond these general neurodegenerative signs, we identify pathognomonic changes in the machinery for protein translation and RNA splicing. Glial fractions showed upregulation of Gpnmb (to 2082%), Cst7, Clec7a, Axl, Csf1, Lgals3, Lgals3bp, Slc11a1, and Usp18 as an unspecific neuroinflammatory signature, versus downregulation of axonal Nefh (to <19%), and synaptic Scn4b, Camk2b, Rab15, and Grin1 mRNAs correlating with circuit disconnection. In all fractions, reductions in Kif5a, Rph3a, and Cplx1 were noted versus disease-specific inductions of ribosomal subunits, presumably mirroring the partial loss-of-function of ATXN2 as RNA translation modulator. Selective accumulations of embryonic factors Rnu1b2 and Eef1a1 versus downregulation of adult Eef1a2 specify the mutation impact on splicing and translation elongation. As a potential underpinning of toxic gain-of-function, the proteostasis transcript Rnf213 appeared increased in astroglial and microglial fractions. These transcriptome data suggest altered ribosomal and spliceosome machinery, with massive microgliosis versus mild astrogliosis, at the core of SCA2 and ALS13.

Keywords:  Miltenyi MACS adult brain separator; RNA-seq; STRING enrichment bioinformatics; U1 3′ stem-loop structure recognition by SMN; fractionation controls Aif1, Gfap, Map2, Cldn5; mRNA circularization; neurofilament loss; translation dynamics; uridine-rich small nuclear RNA

DOI:  https://doi.org/10.3390/cells15080699
Cell Prolif. 2026 Apr 30. e70221

SCD2 Alleviates Diabetes-Associated Cognitive Dysfunction by Improving Microglial Lipid Metabolism.

Yang Yang, Juan He, Jing Zheng, Bing Shao, Lixin Shi, Miao Zhang.

  The mechanisms underlying diabetes-associated cognitive dysfunction (DACD) are not fully understood, and microglial metabolic dysfunction is emerging as a key contributor. This study investigates whether stearoyl-CoA desaturase 2 (SCD2) alleviates cognitive impairment by modulating microglial lipid metabolism and function. Bioinformatics analysis of a single-cell RNA-seq dataset (GSE201644) identified SCD2 downregulation in diabetic (db/db) microglia. A T2D mouse model underwent hippocampal overexpression of SCD2 via AAV injection. In vitro, high glucose (HG)-treated BV2 microglia-like cells were subjected to SCD2 overexpression or oleic acid (OA) supplementation. Mitochondrial function (OCR, ATP, ETC complexes), lipid droplet accumulation (BODIPY, PLIN2), and inflammation (TNF-α, IL-6) were assessed. Cognitive behaviour (MWM, NOR) and neurophysiology (synaptic markers, neuronal survival) were evaluated. Diabetic microglia exhibited reduced SCD2 expression, impaired oxidative phosphorylation and lipid droplet accumulation (LDAM). SCD2 overexpression or OA rescued mitochondrial function, mitigated lipid droplet accumulation and attenuated inflammation. In vivo, hippocampal SCD2 overexpression attenuated neuroinflammation, preserved synaptic integrity and improved cognition in diabetic mice. SCD2 is essential for maintaining microglial lipid and mitochondrial homeostasis in diabetes. Restoring SCD2 function alleviates neuroinflammation and synaptic deficits, thereby rescuing cognitive impairment, highlighting its therapeutic potential for DACD.

Keywords:  SCD2; diabetes‐associated cognitive dysfunction; lipid droplet accumulation; microglia; neuroinflammation; oxidative phosphorylation

DOI:  https://doi.org/10.1111/cpr.70221
CNS Neurosci Ther. 2026 Apr;32(4): e70886

Perivascular SPP1 Drives Microglial Synaptic Engulfment After Ischemic Stroke.

Chenchen Xu, Xiaoxiao Li, Nan Cheng, Rui Zhao, Xin Wang, Wenxin Xia, Jianjian Dong, Yongsheng Han.

   OBJECTIVE: Following ischemic stroke (IS), activated microglia activity could contribute to neuronal injury and blood-brain barrier (BBB) disruption. The upstream vascular-derived signal initiating this transition remains unclear; therefore, we investigated whether perivascular SPP1 regulates microglia-mediated synapse engulfment during IS.
METHODS: Male C57BL/6 mice were assigned to sham, shSpp1, middle cerebral artery occlusion/reperfusion (MCAO/R), and MCAO/R + shSpp1 groups. Cerebral perfusion was assessed using laser speckle contrast imaging and super-resolution vascular imaging, while neuronal injury was evaluated using Nissl and TUNEL staining. Proteomic profiling of the ischemic penumbra identified regulators of microglia-mediated synaptic remodeling. Synaptic structure and glial-vascular unit (GVU) integrity were examined using transmission electron microscopy, immunofluorescence, and molecular analyses. Behavioral outcomes were assessed using the open-field, Barnes maze, rotarod, and wire-hanging tests.
RESULTS: Compared with sham controls, MCAO/R mice displayed increased microglial synaptic engulfment and ultrastructural synaptic damage in the ischemic penumbra, accompanied by reduced synaptic protein expression. Proteomic analysis revealed upregulation of inflammatory and vascular-related pathways, with marked upregulation of SPP derived from perivascular macrophages. Spp1 silencing attenuated neuroinflammation, reduced infarct volume, improved cerebral perfusion, preserved GVU integrity, and alleviated behavioral deficits. Spp1 suppression also reduced microglial synaptic engulfment in vivo and restored synaptic protein and mRNA levels in vitro.
CONCLUSION: Targeting perivascular SPP1 suppresses excessive microglia-mediated synaptic engulfment, preserves BBB integrity and synaptic architecture, and offers a GVU-centered therapeutic strategy for IS.

Keywords:  barrier integrity; glial‐vascular unit; ischemic stroke; microglia synaptic engulfment; perivascular signaling

DOI:  https://doi.org/10.1002/cns.70886
Regen Biomater. 2026 ;13 rbag059

Dual-peptide engineered macrophage membrane biomimetic nanosystem via targeting Rg1 delivery for traumatic brain injury therapy.

Weiquan Liao, Zhichao Lu, Ziheng Li, Chenxing Wang, Xingjia Zhu, Jue Zhu, Yongqi Zhu, Jialiang Lin, Jiajia Wen, Xuanfeng Chen, Jian Chen, Jianhong Shen, Youlang Zhou, Peipei Gong.

  Traumatic brain injury (TBI) induces a detrimental inflammatory microenvironment at the lesion site, which, together with neuronal death and loss, leads to neurological dysfunction. The blood-brain barrier (BBB) further impedes intracerebral drug delivery, posing a major challenge for post-TBI therapy. To overcome this, we developed a brain-targeted biomimetic nanosystem (R/T-MaM-NPs) using an engineered dual-peptide-modified macrophage membrane (MaM). This system encapsulates neuroprotective ginsenoside Rg1 into poly (lactic-co-glycolic acid)-based nanoparticles (NPs). RAW264.7 macrophages were engineered to co-express targeting peptides (RVG and T7) on their membranes; the derived R/T-MaM was then coated onto NPs. The MaM coating conferred high biocompatibility and biosafety, enabling R/T-MaM-NPs to reduce immune clearance and prolong systemic circulation. By leveraging the intrinsic inflammatory chemotaxis of MaM and dual-peptide targeting, the integrated system promoted traversal across the BBB and subsequent accumulation around the cerebral lesion, thereby inducing the transdifferentiation of reactive astrocytes (RAs) into electrophysiologically functional neuron-like cells. RNA sequencing confirmed significant upregulation of neurogenic genes in R/T-MaM-NP-treated RAs, an outcome closely linked to suppression of the Wnt/Notch signaling pathway. Furthermore, R/T-MaM-NPs remodeled the inflammatory microenvironment at the TBI site, alleviated cerebral edema, and enhanced the recovery of cognitive and motor functions in TBI mice.

Keywords:  Ginsenoside Rg1; astrocytes; cell membrane; transdifferentiation; traumatic brain injury

DOI:  https://doi.org/10.1093/rb/rbag059