bims-microg 2025-06-29 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–06–29
25 papers selected by
Marcus Karlstetter, Universität zu Köln

The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway.
Microglia loss triggers glial stress and white matter damage in human leukodystrophy.
Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia.
Mutations in the human CSF1R gene impact microglia's maintenance of brain white matter integrity.
Neutrophil Mobilization Triggers Microglial Functional Change to Exacerbate Cerebral Ischemia-Reperfusion Injury.
Microglia-mediated neurogenesis is linked to cognitive deficits in a two-hit model of maternal immune activation and juvenile stress.
Inhibition of Phosphodiesterase 10A by MP-10 Rescues Behavioral Deficits and Normalizes Microglial Morphology and Synaptic Pruning in A Mouse Model of FOXP1 Syndrome.
Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways.
Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading.
Targeting the RAGE-RIPK1 binding site attenuates diabetes-associated cognitive deficits.
N-Lactoyl-Phenylalanine modulates lipid metabolism in microglia/macrophage via the AMPK-PGC1α-PPARγ pathway to promote recovery in mice with spinal cord injury.
Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro.
Targeting microglial PPARα ameliorates the outcome of ischemic stroke by enhancing interaction with infiltrating peripheral monocytes/macrophages.
Multi-Strain Probiotics Alleviate Food Allergy-Induced Neurobehavioral Abnormalities by Regulating Gut Microbiota and Metabolites.
ETV5 improves ischemic stroke by targeting HACE1/Nrf2 axis to inhibit microglia M1 polarization and neuron pyroptosis.
Temporal Shifts in MicroRNAs Signify the Inflammatory State of Primary Murine Microglial Cells.
Temporal Dynamics of APOE and TREM2 Expression in Microglial Activation of NMOSD Mouse Models.
Microglial α7-Nicotinic Acetylcholine Receptors Are Expressed in Mitochondria Rather Than on the Plasma Membrane: Roles in Mitochondrial Function.
Bone Marrow-Derived Inducible Microglia-like Cells Promote Recovery of Chronic Ischemic Stroke Through Modulating Neuroinflammation in Mice.
Targeting microglia polarization with Chinese herb-derived natural compounds for neuroprotection in ischemic stroke.
GSDME-mediated pyroptosis in microglia exacerbates demyelination and neuroinflammation in multiple sclerosis: insights from humans and cuprizone-induced demyelination model mice.
Large-scale HLA immunopeptidome and interactome profiling in microglia.
Exploring a Novel Anti-Inflammatory Therapy for Diabetic Retinopathy Based on Glyco-Zeolitic-Imidazolate Frameworks.
Retinal Microglia: Revealing New Opportunities for Identifying Early Biomarkers of Diabetic Retinopathy.
Effects of VEGFA and ANGPT2 Antibodies on the Activation of Microglia in the Early Stages of Streptozotocin-Induced Pathogenesis of Diabetic Retinopathy.

Immunity. 2025 Jun 18. pii: S1074-7613(25)00244-4. [Epub ahead of print]

The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway.

Sarah Naguib, Chloe Lopez-Lee, Eileen Ruth Torres, Se-In Lee, Jingjie Zhu, Daphne Zhu, Pearly Ye, Kendra Norman, Mingrui Zhao, Man Ying Wong, Yohannes A Ambaw, Rodrigo Muñoz-Castañeda, Wei Wang, Tark Patel, Maitreyee Bhagwat, Rada Norinsky, Sue-Ann Mok, Tobias C Walther, Robert V Farese, Wenjie Luo, Subhash C Sinha, Zhuhao Wu, Li Fan, Shiaoching Gong, Li Gan.

  The Christchurch mutation (R136S) in the APOE3 (E3S/S) gene is associated with attenuated tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high amyloid burden in the carrier. However, the molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse Apoe with wild-type human APOE3 or APOE3S/S on a tauopathy background. The R136S mutation decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in hippocampal theta and gamma power. Additionally, the R136S mutation reduced interferon responses to tau pathology in both mouse and human microglia, suppressing cGAS-STING pathway activation. Treating E3 tauopathy mice with a cGAS inhibitor protected against tau-induced synaptic loss and induced transcriptomic alterations similar to the R136S mutation across brain cell types. Thus, suppression of the microglial cGAS-STING-interferon (IFN) pathway plays a central role in mediating the protective effects of R136S against tauopathy.

Keywords:  APOE; Alzheimer’s; Christchurch; cGAS; interferon; local field potentials; microglia; neurodegeneration; single-nuclei RNA sequencing; tauopathy

DOI:  https://doi.org/10.1016/j.immuni.2025.05.023
Nat Immunol. 2025 Jun 26.

Microglia loss triggers glial stress and white matter damage in human leukodystrophy.

DOI: https://doi.org/10.1038/s41590-025-02194-8
Nat Immunol. 2025 Jun 24.

Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia.

Hannah D Mason, Yvonne L Latour, Christopher T Boughter, Kory R Johnson, Dragan Maric, Cayce E Dorrier, Vivian A Guedes, Chen Lai, Patrick C Duncker, Alexis M Johnson, Monica Manglani, Jessica M Gill, Daniel P Perl, Martin Meier-Schellersheim, Dorian B McGavern.

Neurodegenerative diseases activate innate and adaptive immune responses that can either slow or accelerate disease progression. Here, we sought to define beneficial immune pressures that emerge during tauopathy development in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of phosphorylated tau (pTau) in the central nervous system and blood. However, over time microglia converted into distressed antigen-presenting cells, acquired neuronal transcripts and were targeted by resident, clonally expanded CD8+ T cells. These cells did not express traditional effector molecules, such as IFNγ, TNF or granzymes a/b/c, but instead deposited granzyme K (GZMK) onto microglia and were regulated by immune checkpoint proteins (TIGIT, PD-1), as blockade of TIGIT and PD-1 enhanced disease progression. GZMK+CD8+ T cells also targeted microglia in pTau-rich human brain lesions resulting from age, Alzheimer's disease or chronic traumatic encephalopathy. Deletion of CD8+ T cells in mice promoted the emergence of distressed microglia containing neuronal transcripts, markedly enhanced pTau spread and accelerated neurological decline. These data demonstrate that GZMK+CD8+ T cells are a signature of tauopathy development and could potentially be harnessed to slow disease progression.

DOI: https://doi.org/10.1038/s41590-025-02198-4
Nat Immunol. 2025 Jun 26.

Mutations in the human CSF1R gene impact microglia's maintenance of brain white matter integrity.

Siling Du, Yingyue Zhou, Dian Li, Julia Lier, Marina Cella, Mari Tada, Hideomi Hamasaki, Junjie Wu, Zhangying Cai, Jennifer L Orthmann-Murphy, Akiyoshi Kakita, Jonathan Kipnis, Caroline G Bergner, Marco Colonna.

Microglia, the brain's resident macrophages, depend on interleukin-34 and colony-stimulating factor 1 (CSF1) for their development and maintenance, engaging the CSF1 receptor (CSF1R). Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disorder affecting the brain's white matter, is caused by heterozygous pathogenic mutations in the CSF1R gene. This study investigated molecular mechanisms underlying ALSP using single-nucleus RNA sequencing on postmortem brain specimens. Results showed a significant reduction in microglia in ALSP brains, with remaining cells exhibiting a unique activation signature. This reduction correlated with decreased myelinating oligodendrocytes (OLs) and increased neuropilin-2+ OLs with a stress-response and anti-apoptotic signature, driven by STAT3 and fibroblast growth factor receptor pathways. Additionally, astrocytes displayed maladaptive activation and stress responses. These findings underscore microglia's crucial role in supporting OL myelination and limiting astrocyte repair responses, suggesting therapeutic strategies balancing CSF1R, fibroblast growth factor receptor and STAT3 pathways for ALSP and other genetically caused microgliopathies.

DOI: https://doi.org/10.1038/s41590-025-02195-7
Adv Sci (Weinh). 2025 Jun 25. e03722

Neutrophil Mobilization Triggers Microglial Functional Change to Exacerbate Cerebral Ischemia-Reperfusion Injury.

Huijuan Jin, Zhifang Li, Senwei Tan, Qinghui Xiao, Qingcan Li, Jiao Ye, Yifan Zhou, Yan Wan, Qiang Liu, Bijoy K Menon, Bo Hu.

  Acute ischemic stroke is a leading cause of mortality and disability worldwide. Neuroinflammation following ischemia-reperfusion plays a critical role in the disease's pathogenesis. Neutrophil aggregation and clearance within the brain parenchyma influence neuroinflammatory damage during ischemic stroke. Microglia-mediated phagocytosis plays a pivotal role in mitigating neuroinflammation and promoting brain parenchyma recovery. However, the mechanisms underlying the cross-talk between neutrophils and microglia remain poorly understood. Here, this study demonstrates that neutrophils can trigger microglial functional change to inhibit microglial phagocytosis and promote pyroptosis, which is regulated by neutrophil-derived myeloid-related protein 14. Additionally, interleukin-1β released by pyroptotic microglia further upregulates myeloid-related protein 14 expression and facilitates neutrophil mobilization from the bone marrow, establishing a self-sustaining inflammatory loop. Therefore, neutrophils accumulate in the brain parenchyma and further exacerbate microglial neuroinflammation in the ischemic brain. These findings reveal a previously unknown interaction between neutrophils and microglia after acute ischemic stroke and suggest that targeting myeloid-related protein 14 may provide a novel therapeutic strategy for ischemic stroke therapy.

Keywords:  ischemia‐reperfusion injury; microglial phagocytosis; microglial pyroptosis; neutrophil

DOI:  https://doi.org/10.1002/advs.202503722
Brain Behav Immun. 2025 Jun 25. pii: S0889-1591(25)00250-8. [Epub ahead of print]

Microglia-mediated neurogenesis is linked to cognitive deficits in a two-hit model of maternal immune activation and juvenile stress.

Qiuying Zhao, Jiutai Wang, Yue Han, Wan Yan, Shuo Yan, Lei Xie, Zili You.

  Maternal immune activation (MIA), combined with exposure to a second environmental stressor, contributes to neurodevelopmental disorders in offspring. Immune-challenged microglial cells play a crucial role in the pathogenesis of these disorders. However, the mechanisms through which microglia mediate cognitive impairments in individuals exposed to dual stresses remain poorly understood. In this research, pregnant rat dams were subjected to viral mimetic, poly(I:C), and their young male offspring were either exposed to a second stressor or not during juvenile age. The results showed that a pathological microglial phenotype was accompanied by impairments in hippocampal neurogenesis and deficits in hippocampus-dependent spatial learning and memory in the MIA offspring exposed to the second stressor during juvenile age. Minocycline shifts pathological microglial cells to a neuroprotective state, alleviating neurogenesis impairments and spatial learning and memory deficits in these "two-hit" animals. However, the cognitive improvements induced by minocycline were blocked by temozolomide treatment, as evidenced by the inhibition of neurogenesis. Our findings highlight the important role of hippocampal neurogenesis in inflammatory-mediated cognitive abnormalities and provide insights into the roles of microglia underlying neurodevelopmental disorders.

Keywords:  Cognitive impairments; Hippocampal neurogenesis; Microglial phenotype; Minocycline; Two-hit stress

DOI:  https://doi.org/10.1016/j.bbi.2025.06.032
Adv Sci (Weinh). 2025 Jun 26. e00623

Inhibition of Phosphodiesterase 10A by MP-10 Rescues Behavioral Deficits and Normalizes Microglial Morphology and Synaptic Pruning in A Mouse Model of FOXP1 Syndrome.

Henning Fröhlich, Jing Wang, Ferdinand Althammer, Tim Schubert, Nina Kluck, Valery Grinevich, Stefanie Schmitteckert, Christian P Schaaf, Gudrun A Rappold.

  FOXP1 syndrome caused by FOXP1 haploinsufficiency is characterized by intellectual disability, speech, and language impairment, autistic features, and neuropsychiatric abnormalities such as anxiety and hyperactivity. Behavioral changes in patients are mirrored in Foxp1± mice. It is shown that decreased Foxp1 in the Foxp1± striatum results in a significant decrease in phosphodiesterase 10a (Pde10a). Predominantly expressed in medium spiny neurons (MSNs), Pde10a modulates basal ganglia circuitry. Furthermore, the Foxp1± striatum exhibits microglial activation, reduced synaptic pruning, and dysregulation of 111 inflammatory genes. These include the downregulated P2ry12 and Fcrls, markers of homeostatic microglia, and upregulated Cd74, a marker of reactive microglia, suggesting that neuroinflammation contributes to the observed deficits. Interestingly, treatment of Foxp1± mice with the PDE10A antagonist MP-10 (PF-2545920) immediately after birth not only corrects behavioral abnormalities, including decreased ultrasonic vocalization, hyperactivity, and anxiety but also normalizes changes in microglia morphology and synaptic pruning. Transcriptomic analysis with a neuroinflammation-specific gene panel reveals nominal gene expression changes after MP-10 treatment, including Bdnf upregulation and enrichment of neurotrophin signaling. Since FOXP1 and its signaling pathway are highly conserved, administration of MP-10 or other Pde10a antagonists may also alleviate the neurological dysfunction seen in humans with FOXP1 syndrome.

Keywords:  FOXP1 syndrome; MP‐10 (PF‐2545920); Pde10a; mouse model; treatment

DOI:  https://doi.org/10.1002/advs.202500623
Alzheimers Dement. 2025 Jun;21(6): e70377

Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracellular signaling pathways.

Alzheimer's Disease Genetics Consortium (ADGC), Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight‐ADRC)

   INTRODUCTION: Most genetic studies for Alzheimer's disease (AD) have been focused on late-onset AD (LOAD). There are no large genetic studies on early-onset AD (EOAD).
METHODS: We performed a multi-ancestry (non-Hispanic European, African, and East Asian) genome-wide association study (GWAS) including a total of 7,349 cases and 17,887 control. Cases with age at onset younger than 70 years were included. Sensitivity analysis including cases with onset <65 was performed. Only controls older than 70 were included to decrease the risk of developing LOAD.
RESULTS: We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and functional annotations, we nominate eight novel genes that are involved in microglia activation, glutamate production, and signaling pathways.
DISCUSSION: EOAD, although sharing genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification.
HIGHLIGHTS: We performed the largest and first multi-ethnic genetic screening for early-onset Alzheimer's disease (AD). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. The novel genes are implicated microglia activation, glutamate production, and signaling pathways. EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.

Keywords:  ADGC; Alzheimer's disease risk; GWAS; early onset Alzheimer's disease; genetic ancestry; gene‐mapping; late onset Alzheimer's disease; meta‐analysis; multi‐ancestry

DOI:  https://doi.org/10.1002/alz.70377
J Neuroinflammation. 2025 Jun 27. 22(1): 166

Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading.

Xiaoli Liu, Huijin Wang, Xi Tian, Yingqi Luo, Minmin Ma, Zilong Zheng, Yaping Wang, Shi Feng, Qiushi Wang, Zhuo Xu, Wen Yao, Siqiang Ren.

  Depression has been widely recognized as an important accelerating factor contributing to the aggravation of cognitive decline in Alzheimer's disease (AD) patients. Previous studies show that microglia-mediated neuroinflammation is a common and critical event in the etiology of both depression and dementia, but whether and how microglia participate in the process of depression-exacerbating AD pathology is largely unknown. By establishing the learned helplessness depression model on 5×FAD mice, we confirmed that depression can indeed promote Aβ plaque deposition and deteriorate the cognitive performance of the AD mice. Importantly, we found that microglial lactate concentration is dramatically increased in the depressed AD brain, leading to activation of potassium channel Kv1.3 likely through non-direct-lactylation. The activated Kv1.3 further facilitates Aβ-containing exosome spreading from microglia in the vicinity of Aβ plaque into the surrounding brain tissue. Notably, conditional knock-out of Kv1.3 in microglia can reverse the depression-induced acceleration of AD pathology and cognitive decline. Together, our study highlights an important function of microglia Kv1.3 in the promotion of Aβ propagation in the context of depression-exacerbating AD pathology.

Keywords:  Alzheimer’s disease; Aβ spreading; Depression; Exosomes; Kv1.3; Lactate

DOI:  https://doi.org/10.1186/s12974-025-03488-2
J Neuroinflammation. 2025 Jun 21. 22(1): 162

Targeting the RAGE-RIPK1 binding site attenuates diabetes-associated cognitive deficits.

Lin Gao, Shidi Wu, Bin Hu, Qiuyu Zhang, Yifei Wu, Hui Li, Ye Qian, Chengyu Huang, Xiangru Wen, Hui Li, Aifang Cheng, Yuanjian Song, Changjiang Ying, Xiaoyan Zhou.

  Microglial activation can cause neuroinflammation and the consequent neurological impairments play prominent roles in diabetes-associated cognitive deficits. Receptor-interacting protein kinase 1 (RIPK1) phosphorylation is involved in this deleterious microglial activation, but the exact molecular mechanisms are not clear. Here, RIPK1 expression was increased in diabetic patients with cognitive impairment. Furthermore, in diabetic mice, RIPK1 death domain directly binds to C-terminal of the receptor for advanced glycation end products (ctRAGE) could regulate RIPK1 phosphorylation in microglia. This RAGE-RIPK1 complex activates inflammatory signaling, resulting in cascades that ultimately promote cognitive impairment in diabetic mice. An engineered brain-targeting RIPK1 peptide blocked binding of RIPK1 to RAGE, which inhibited RIPK1 phosphorylation, decreased neuroinflammation, improved neuronal morphology and function, and prevented diabetes-associated cognitive deficits in mice. This study uncovers a previously unknown mechanism of neuroinflammation and suggests a novel therapeutic avenue for treating cognitive deficits induced by hyperglycemia.

Keywords:  Diabetes-associated cognitive deficits; Neuroinflammation; RIPK1 peptide; Receptor-interacting protein kinase 1; The receptor for advanced glycation end products

DOI:  https://doi.org/10.1186/s12974-025-03489-1
J Neuroinflammation. 2025 Jun 27. 22(1): 167

N-Lactoyl-Phenylalanine modulates lipid metabolism in microglia/macrophage via the AMPK-PGC1α-PPARγ pathway to promote recovery in mice with spinal cord injury.

Weiyang Ying, Weidong Weng, Peifang Wang, Chi Pan, Jiani Qiu, Qianqian Huang, Gonghao Zhan, Xiaoli Chen.

The accumulation of lipids in microglia/macrophage-induced inflammation exacerbation represents a pivotal factor contributing to secondary injury following spinal cord injury (SCI). N-Lactoyl-Phenylalanine (L-P), a metabolic byproduct of exercise, exhibits the capacity to regulate carbohydrate and lipid metabolism and may serve as a potential regulator of lipid metabolism in microglia/macrophage. This study investigates the role of L-P in modulating lipid homeostasis in microglia/macrophage and its therapeutic implications for SCI recovery. By establishing a mouse model of SCI, we confirmed that L-P administration markedly altered lipid metabolism in microglia/macrophage. This metabolic reprogramming was mediated through the activation of the AMPK-PGC1α-PPARγ signaling pathway, which plays a crucial role in regulating cellular energy metabolism and inflammatory responses. Our findings demonstrate that L-P treatment enhances the lipid metabolic capacity of microglia/macrophage, thereby attenuating neuroinflammation and promoting tissue repair after injury. Moreover, the polarization of microglia/macrophage shifts toward the anti-inflammatory M2 phenotype, providing substantial support for the regenerative process of the injured spinal cord. Functional analysis revealed that mice treated with L-P exhibited significantly improved motor function compared to the control group. Collectively, these results underscore the therapeutic potential of L-P in SCI and suggest its utility as a metabolic intervention strategy by modulating microglia/macrophage lipid metabolism to accelerate recovery.

DOI: https://doi.org/10.1186/s12974-025-03495-3
Cell Rep. 2025 Jun 25. pii: S2211-1247(25)00680-1. [Epub ahead of print]44(7): 115909

Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro.

Anna Podleśny-Drabiniok, Carmen Romero-Molina, Tulsi Patel, Wen Yi See, Yiyuan Liu, Edoardo Marcora, Alison M Goate.

  Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer's disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (interleukin [IL]-4, CSF1, IL-34, and transforming growth factor-β) reprograms human THP-1 macrophages toward AD-relevant phenotypes. This treatment induces significant transcriptomic changes, driving THP-1 macrophages toward a transcriptional state reminiscent of disease-associated microglia and lipid-associated macrophages (LAM), collectively referred to as DLAM. Transcriptome profiling reveals gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing shows an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrate alterations in cell motility, phagocytosis, lysosomal activity, and metabolic profiles. These findings provide insights into cytokine-mediated reprogramming of macrophages toward disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.

Keywords:  Alzheimer’s disease; CP: Immunology; CP: Neuroscience; DAM; IL-4; LAM; THP-1 macrophages; disease-associated microglia; efferocytosis; lipid-associated macrophages

DOI:  https://doi.org/10.1016/j.celrep.2025.115909
Cell Rep. 2025 Jun 20. pii: S2211-1247(25)00646-1. [Epub ahead of print]44(7): 115875

Targeting microglial PPARα ameliorates the outcome of ischemic stroke by enhancing interaction with infiltrating peripheral monocytes/macrophages.

Tong Ren, Maoshu Zhu, Xilin Jiang, Lanxi Xu, Hao Jin, Yu Zhou, Yun Zhao, Rengong Zhuo, Wenjun Li, Caixia Chen, Lu Peng, Xin Jin, Ying Li, Lichao Yang.

  The interaction between infiltrating immune cells and brain-resident cells is critical for inducing an inflammatory response to ischemic stroke. However, the direct effects of CD11b+CD45int microglia in the brain on infiltrating CD11b+CD45highLy6G- monocytes/macrophages (Mos/MΦs) and the precise molecular mechanisms underlying these effects after acute ischemic stroke (AIS) remain unknown. Here, ischemia-induced microglial peroxisome proliferator-activated receptor-alpha (PPARα) downregulation was found to be critical for enhancing the inflammatory response and exacerbating ischemic brain injury by priming peripheral pro-inflammatory Mo/MΦ infiltration. The targeted microglial PPARα signal exerted neuroprotective effects on ischemic stroke by protecting blood-brain barrier (BBB) integrity and inhibiting the infiltration of innate immune cells. Furthermore, overexpression of microglia-specific PPARα exerted neuroprotective effects by enhancing the interleukin (IL)-4 signal-mediated crosstalk of microglia-MΦs. Therefore, our study reveals that ischemia-induced microglial PPARα deficiency expands the inflammatory response and exacerbates ischemic brain injury by enhancing the interaction with infiltrating peripheral Mos/MΦs and suggests that targeting microglial PPARα is a potential therapeutic strategy for improving acute cerebral ischemic injury.

Keywords:  CP: Immunology; CP: Neuroscience; PPARα; innate immune; ischemic stroke; microglia; monocytes/macrophages

DOI:  https://doi.org/10.1016/j.celrep.2025.115875
Nutrients. 2025 Jun 08. pii: 1955. [Epub ahead of print]17(12):

Multi-Strain Probiotics Alleviate Food Allergy-Induced Neurobehavioral Abnormalities by Regulating Gut Microbiota and Metabolites.

Shouxun Hu, Luanluan Li, Chunyan Zhou, Yue Zhang, Xiaodan Yu.

  Background and aim: Neurobehavioral changes associated with food allergies have been reported, but the therapeutic effects of probiotics have not been fully explored. Our study aimed to investigate the impact of multi-strain probiotics on neurobehavioral outcomes and to elucidate the underlying mechanism via the microbiota-gut-brain axis. Methods: C57BL/6J Male mice were randomly divided into the following three groups: (1) control group; (2) OVA-sensitized group; (3) OVA-sensitized group treated with multi-strain probiotics (OVA + P). Anaphylactic reactions and behavioral abnormalities were assessed by histological, immunological, and behavioral analyses. To further elucidate the underlying mechanisms, the prefrontal cortex was collected for microglial morphological analysis, while serum and fecal samples were obtained for untargeted metabolomic profiling and 16S rDNA-based gut microbiota analysis, respectively. Results: Multi-strain probiotics significantly alleviated anaphylactic reactions in OVA-sensitized mice, as evidenced by reduced serum IgE levels, decreased Th2 cytokines, and reduced epithelial damage. Meanwhile, neurobehavioral symptoms were alleviated, including anxiety-like and depression-like behaviors, repetitive behaviors, social avoidance, and impaired attention. Mechanistically, probiotics administration suppressed production of inflammatory cytokines (TNF-α, IL-1β and IL-6) and inhibited activation of M1 microglia in the prefrontal cortex, which might contribute to neuron recovery. Furthermore, multi-omics analysis revealed that amino acid metabolism restoration in OVA + P mice, particularly carboxylic acids and derivatives, which was remarkably correlated with alterations in gut microbiota and behaviors related to FA. Conclusions: Gut microbiota and its amino acid metabolites mediate the therapeutic effects of multi-strain probiotics on FA-induced behavioral abnormalities. These effects occur alongside the suppression of neuroinflammation and microglial activation in the prefrontal cortex. Our findings highlight the neuroimmune regulatory role of the gut-microbiota-brain axis and support the potential use of probiotics as an intervention for FA-induced brain dysfunctions.

Keywords:  amino acids metabolism; food allergy; gut microbiota; metabolomics; neurobehavior; probiotics

DOI:  https://doi.org/10.3390/nu17121955
Biochem Pharmacol. 2025 Jun 23. pii: S0006-2952(25)00322-3. [Epub ahead of print] 117057

ETV5 improves ischemic stroke by targeting HACE1/Nrf2 axis to inhibit microglia M1 polarization and neuron pyroptosis.

Delong Meng, Qian Su, Kejuan Jia, Mengjie Jin, Wenting Liu, Shiqi Yang, Zhiqiang Su.

  Ischemic stroke is a kind of cerebrovascular disease with high mortality. The expression of ETS variant transcription factor 5 (ETV5) is down-regulated in ischemic stroke, but the specific role and mechanism remain unclear. In this study, the effects of ETV5 on ischemic stroke were investigated in vivo and in vitro by establishing the middle cerebral artery occlusion/reperfusion (MCAO/R) animal model and oxygen-glucose deprivation/reoxygenation (OGD/R) microglia model, respectively. We found that ETV5 reduced the infarct size, neurological deficit, microglia M1 polarization, and neuron pyroptosis level. Mechanistically, we further examined the expression of the HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1 (HACE1) and nuclear factor erythroid 2-related factor 2 (Nrf2) based on animal and cellular models to assess whether ETV5 affects ischemic stroke through the HACE1/Nrf2 signaling pathway. We found that ETV5 promoted the expression of HACE1 and Nrf2 in microglia and that HACE1 was transcriptionally activated by ETV5, which in turn competed with the E3 ligase KEAP1 for binding of Nrf2 and enhances the protein stability and nuclear expression of Nrf2. Our results suggest that ETV5 can ameliorate brain injury caused by ischemic stroke and this is closely related to inducing the HACE1/Nrf2 pathway to inhibit microglia M1 polarization.

Keywords:  ETV5; HACE1; Ischemic stroke; M1 microglia; Nrf2

DOI:  https://doi.org/10.1016/j.bcp.2025.117057
Int J Mol Sci. 2025 Jun 13. pii: 5677. [Epub ahead of print]26(12):

Temporal Shifts in MicroRNAs Signify the Inflammatory State of Primary Murine Microglial Cells.

Keren Zohar, Elyad Lezmi, Fanny Reichert, Tsiona Eliyahu, Shlomo Rotshenker, Marta Weinstock, Michal Linial.

  The primary function of microglia is to maintain brain homeostasis. In neurodegenerative diseases like Alzheimer's, microglia contribute to neurotoxicity and inflammation. In this study, we exposed neonatal murine primary microglial cultures to stimuli mimicking pathogens, injury, or toxins. Treatment with benzoyl ATP (bzATP) and lipopolysaccharide (LPS) triggered a coordinated increase in interleukin and chemokine expression. We analyzed statistically significant differentially expressed microRNAs (DEMs) at 3 and 8 h post-activation, identifying 33 and 57 DEMs, respectively. Notably, miR-155, miR-132, miR-3473e, miR-222, and miR-146b showed strong temporal regulation, while miR-3963 was sharply downregulated by bzATP. These DEMs regulate inflammatory pathways, including TNFα and NFκB signaling. We also examined the effect of ladostigil, a neuroprotective agent known to reduce oxidative stress and inflammation. At 8 h post-activation, ladostigil induced upregulation of anti-inflammatory miRNAs, such as miR-27a, miR-27b, and miR-23b. Our findings suggest that miRNA profiles reflect microglial responses to inflammatory cues and that ladostigil modulates these responses. This model of controlled microglial activation offers a powerful tool with which to study inflammation in the aging brain and the progression of neurodegenerative diseases.

Keywords:  CLIP-Seq; IL-1; RNA-seq; TarBase; cytokines; inflammation; innate immune system; miRBase; purinergic receptor

DOI:  https://doi.org/10.3390/ijms26125677
Mol Neurobiol. 2025 Jun 23.

Temporal Dynamics of APOE and TREM2 Expression in Microglial Activation of NMOSD Mouse Models.

Si Xu, Wentao Dai, Tianfeng Wang, Shugang Cao, Jing Du, Xiaonan Pang, Qi Li, Yanghua Tian.

  Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune demyelinating disease characterized by recurrent neuroinflammation and disability. Microglial activation plays a critical role in NMOSD pathogenesis, yet the mechanisms regulating its temporal dynamics remain poorly understood. The interplay between apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), key regulators of microglial function in neurodegenerative diseases, has not yet been explored in NMOSD. We conducted bulk RNA-seq in NMOSD mouse models and integrated transcriptomic sequencing, bioinformatics, and machine learning (LASSO, SVM-RFE, random forest) to identify microglia-associated hub genes in an NMOSD mouse model. Immune cell infiltration was analyzed via ImmuCC. Candidate genes were validated using Western blotting and immunofluorescence. Temporal microglial activation and APOE/TREM2 expression were assessed at 3, 7, and 10 days postmodeling. Transcriptomic analysis identified 94 microglia-associated differentially expressed genes (MDEGs), with APOE and TREM2 emerging as central hubs through machine learning. ImmuCC revealed significant infiltration of macrophages, likely indicating microglial polarization. APOE and TREM2 expression peaked on day 3 postinduction, which was correlated with maximal microglial activation (IBA1 +), followed by a gradual decrease. Experimental validation confirmed elevated APOE and TREM2 protein levels in NMOSD mice, with immunofluorescence showing colocalization in activated microglia. This study establishes the APOE-TREM2 axis as a critical regulator of microglial activation in NMOSD, exhibiting early proinflammatory and later reparative roles. The biphasic expression pattern aligns with microglial phenotypic switching, suggesting therapeutic potential for stage-specific interventions. Our findings bridge computational predictions with experimental validation, offering novel insights into NMOSD mechanisms and actionable targets for therapy.

Keywords:  APOE; Machine learning; Microglia; NMOSD; Sequencing; TREM2

DOI:  https://doi.org/10.1007/s12035-025-05160-5
J Neurochem. 2025 Jun;169(6): e70139

Microglial α7-Nicotinic Acetylcholine Receptors Are Expressed in Mitochondria Rather Than on the Plasma Membrane: Roles in Mitochondrial Function.

Yoki Nakamura, Riku Matsuda, Shogo Kuribayashi, Masatoshi Takemura, Kazue Hisaoka-Nakashima, Norimitsu Morioka.

  The subcellular localization and cellular functions of the microglial α7-nicotinic acetylcholine receptor (α7-nAChR) were investigated in detail. Although α7-nAChR mRNA was present in microglia isolated from mouse brains by fluorescence-activated cell sorting, we observed low levels of mRNA for NACHO (novel acetylcholine receptor chaperone) and RIC3 (resistance to inhibitors of cholinesterase 3), which are crucial chaperones for the functional expression of α7-nAChR as an ionotropic receptor. Limited localization of α7-nAChR on the cell membrane of isolated microglia suggested an intracellular distribution of this receptor preferentially. To examine the function of α7-nAChR as a ligand-gated ion channel receptor, we treated primary cultured microglia with the α7-nAChR agonist choline; however, no increase in the intracellular calcium ion concentration was observed. Cell staining with α-bungarotoxin and an α7-nAChR antibody suggested that the α7-nAChR expressed in microglia is localized intracellularly, particularly in mitochondria, rather than at the cell membrane. Treatment of primary cultured microglia with choline significantly increased intracellular ATP levels, an indicator of mitochondrial function. This increase in ATP production was significantly suppressed by pretreatment with the α7-nAChR antagonist methyllycaconitine. In microglia with relatively low expression levels of NACHO and RIC3, the population of α7-nAChRs functioning as ion channel receptors at the plasma membrane is expected to be limited. This study reveals a newly described cellular function of microglial α7-nAChR in mitochondria. This finding improves our understanding of the multifaceted roles of α7-nAChRs in the central nervous system and opens new avenues for exploring their potential as a therapeutic target in microglia-related central nervous system disorders.

Keywords:  ATP; NACHO; microglia; mitochondria; α7‐nicotinic acetylcholine receptor

DOI:  https://doi.org/10.1111/jnc.70139
Biomedicines. 2025 May 30. pii: 1347. [Epub ahead of print]13(6):

Bone Marrow-Derived Inducible Microglia-like Cells Promote Recovery of Chronic Ischemic Stroke Through Modulating Neuroinflammation in Mice.

Bach Ngoc Nguyen, Tomoaki Kitamura, Shuhei Kobashi, Makoto Urushitani, Tomoya Terashima.

  Background: Chronic ischemic stroke presents a significant challenge in neurology, with limited therapeutic options available for long-term recovery. During cerebral infarction, anti-inflammatory phenotype microglia/macrophages produce anti-inflammatory cytokines and neurotrophic factors that facilitate the process of brain repair. However, obtaining sufficient anti-inflammatory microglia/macrophages from the human central nervous system is challenging. Bone marrow-derived inducible microglia-like cells (BM-iMGs) with an anti-inflammatory microglial phenotype were explored to induce neuroprotective properties. Here, we transplanted BM-iMGs into the brain of middle cerebral artery occlusion (MCAO) model male mice to explore their potential for treating chronic ischemic stroke. Methods: Bone marrow-derived mononuclear cells (BM-MNCs) were isolated from green fluorescent protein mice and incubated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 to induce BM-iMGs with an anti-inflammatory phenotype. BM-iMGs were transplanted into the brains of mice on day 14 after MCAO, and behavioral tests, histology, cerebral blood flow, and gene expression were evaluated. Results: An intracranial injection of BM-iMGs promoted neurobehavioral recovery, reduced neuronal cell loss, suppressed neuroinflammatory astrocytic and microglial responses in the brain, and increased cortical surface cerebral blood flow in MCAO mice. Furthermore, neuroprotective genes were upregulated, whereas proinflammatory genes were downregulated. Conclusions: The intracranial injection of BM-iMG cells shows significant potential as a novel therapy for chronic ischemic stroke.

Keywords:  BM-iMG cells; cell therapy; cerebral blood flow; chronic ischemic stroke; microglia; neuroinflammation

DOI:  https://doi.org/10.3390/biomedicines13061347
Front Cell Dev Biol. 2025 ;13 1580479

Targeting microglia polarization with Chinese herb-derived natural compounds for neuroprotection in ischemic stroke.

Lu Yu, Yin Dong, Mincheng Li, Huifang Liu, Cuina Yan, Xiaoxian Li, Yuehua Gu, Liwei Wang, Chuan Xu, Jie Xu, Zhen Yuan, Ming Xia, Jiwei Cheng.

  Given that ischemic stroke ranks as one of the most fatal diseases globally, it is imperative to develop clinically effective neuroprotective agents for stroke. Microglia serve as innate immune cells for maintaining brain homeostasis, and upon activation, they are well-known to be able to transform into two functional phenotypes, namely, the M1 and M2 types, which can convert each other and exert opposing effects on neurotoxicity and neuroprotection, respectively. Traditional Chinese medicine possesses a deep-rooted and profound history with rich theory in treating cerebrovascular disorders, and its natural compounds have been considered as promising adjunctive therapies. Recently, researchers have been devoting attention to the inflammation-suppressive properties of the compounds from Chinese herbs. These compounds are gradually emerging as adoptable therapeutic agents with wide application prospect for improving stroke outcomes, through regulating microglial polarization to attenuate neuroinflammation. Thereby, we reviewed the functions of microglial cells in inflammation and neuroprotection and explored the regulation of microglial activity by natural compounds to alleviate neuroinflammation and protect neural function after ischemic stroke. Collectively, using natural compounds to suppress the microglia-mediated detrimental inflammatory response, meanwhile enhancing their anti-inflammatory abilities to accelerate neuronal recovery, will be promising therapeutic approaches for ischemic stroke.

Keywords:  ischemic stroke; microglia; natural compounds; neuroinflammation; traditional Chinese herbs

DOI:  https://doi.org/10.3389/fcell.2025.1580479
Cell Death Differ. 2025 Jun 25.

GSDME-mediated pyroptosis in microglia exacerbates demyelination and neuroinflammation in multiple sclerosis: insights from humans and cuprizone-induced demyelination model mice.

Danjie Wang, Tongtong Zhang, Qi Shao, Xinyi Wu, Xiaoqiang Zhao, Hongyu Zhang, Yumeng Wang, Jingxian Sun, Xuechun Chang, Keying Zhu, Shuai Wu, Li Cao, Wankun Chen, Jun Wang.

Demyelination, a hallmark of multiple sclerosis (MS), disrupts neural conduction due to myelin sheath degradation. Microglia-mediated inflammation plays a pivotal role in this process, with emerging evidence implicating gasdermin E (GSDME) in neuroinflammation and neurodegeneration. However, the specific role of GSDME in MS remains unclear. Here, we investigated the involvement of GSDME in MS using brain tissues from MS patients and cuprizone (CPZ)-induced demyelination model mice. We observed elevated GSDME expression in the central nervous system (CNS) lesions of MS patients, with pronounced GSDME cleavage in microglia at injury sites. Genetic knockout of Gsdme alleviated CPZ-induced motor deficits, demyelination, and neuroinflammation. Furthermore, caspase-3 inhibition significantly suppressed GSDME activation, resulting in reduced demyelination, motor coordination impairment, and neuroinflammation. In an experimental autoimmune encephalomyelitis (EAE) model, caspase-3/GSDME-mediated microglial pyroptosis critically mediated the progression of neuroinflammation and white matter demyelination. Transcriptome sequencing revealed that GSDME regulated the expression of genes related to disease-associated microglia (DAMs) and impaired microglial autophagy, a process critical for myelin debris clearance. Gsdme knockout downregulated the expression of genes associated with DAMs and CPZ-induced microglia-driven demyelination while increasing the expression of remyelination-related genes (Cybb and Cd74). In vitro, GSDME suppression promoted microglial autophagy and myelin debris clearance. Collectively, our findings highlight GSDME-mediated pyroptosis as a key driver of demyelination and neuroinflammation in MS, suggesting novel therapeutic targets for neuroinflammatory disorders.

DOI: https://doi.org/10.1038/s41418-025-01537-0
bioRxiv. 2025 Apr 26. pii: 2025.04.23.650327. [Epub ahead of print]

Large-scale HLA immunopeptidome and interactome profiling in microglia.

Sydney Klaisner, Ying Hao, Alexandra Beilina, Jae-Hyeon Park, Ziyi Li, Michiyo Iba, Cole Tindall, Benjamin Jin, Jacob Epstein, Isabelle Kowal, Caroline B Pantazis, Nicole Carmiol, Paige Jarreau, Nicole Washecka, Cory Weller, Mike A Nalls, Kendall Van Keuren-Jensen, Andrew B Singleton, Mark R Cookson, Yue Andy Qi.

Microglia are immune cells of the brain and act as major antigen presenting cells. Antigen presentation involves the human leukocyte antigen (HLA) complex, which is implicated in genetic risk of multiple neurodegenerative diseases. How HLA affects the function of microglia in the context of neurodegenerative disease remains unclear. Here, we investigated the HLA epitopes and their protein interactome in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGLs) using systematic mass spectrometry (MS)-based immunopeptidomics, whole-cell proteomics, affinity purification, and prediction algorithms. Our results revealed the presence of almost 7,000 peptides presented by HLA class I and II within microglia. We further showed that the immunopeptidome landscapes of iPSCs, iMGLs and interferon-gamma (IFNγ) stimulated iMGLs are all readily distinguishable. Furthermore, HLA interacts with different groups of proteins in iPSCs compared to iMGLs which involve proteins in immune response. Importantly, we detected 25 HLA epitopes derived from 15 genes associated with Alzheimer's and related dementias such as Tau, PLD3 (Alzheimer's disease), TDP-43, FUS (Frontotemporal dementia), and PARK7, VPS35 (Lewy Body dementia). We predicted 31 mutant epitopes derived from these ADRD genes that could be presented with strong interaction to HLA molecules. Along with these epitopes, we observed an enrichment of immune-related interaction proteins in microglia treated with IFNγ. These results provide evidence that aggregated and mutated proteins can interact with HLA alleles and be presented on the cell surface by microglia cells. This study sheds light on the antigen presenting and adaptive immunity mechanism within the central nervous system and its possible effects on neurodegenerative diseases.

DOI: https://doi.org/10.1101/2025.04.23.650327
Pharmaceutics. 2025 Jun 17. pii: 791. [Epub ahead of print]17(6):

Exploring a Novel Anti-Inflammatory Therapy for Diabetic Retinopathy Based on Glyco-Zeolitic-Imidazolate Frameworks.

Elena Díaz-Paredes, Francisco Martín-Loro, Rocío Rodríguez-Marín, Laura Gómez-Jaramillo, Elena M Sánchez-Fernández, Carolina Carrillo-Carrión, Ana I Arroba.

  Background/Objectives: Diabetic retinopathy is an ocular disease caused by changes in the expression of inflammatory mediators and increased oxidative stress in the retina and is the leading cause of vision loss in diabetic patients. Currently, there is no treatment capable of reversing retinal damage, which represents a significant burden on the quality of life of patients. (1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin stands outs as a prototype of the sp2-iminoglycolipids family for its beneficial neuroprotective effect against this chronic eye disease. Critical issues related to the low solubility and bioavailability of this glycolipid in biological settings are overcome by its encapsulation in a Zeolitic-Imidazolate Framework (ZIF) structure, resulting in homogeneous and biocompatible GlycoZIF nanoparticles. Cell studies show an enhanced cellular uptake compared with the free glycolipid, and importantly, its bioactivity is preserved once released inside cells. Methods: Extensive in vitro and ex vivo assays with diabetic retinopathy models unveil the mechanistic pathways of the designed GlycoZIF. Results: A reduction in proinflammatory mediators, increased heme oxygenase-1 level, inhibition of NLRP3 inflammasome, and reduced reactive gliosis is shown. Conclusions: These findings demonstrate for the first time the potential of Glyco-modified ZIFs for the treatment of diabetes-related ocular problems by controlling the immune-mediated inflammatory response.

Keywords:  diabetic retinopathy; glycolipid; immune-mediated therapy; inflammation; microglia; zeolitic-imidazolate framework

DOI:  https://doi.org/10.3390/pharmaceutics17060791
Curr Eye Res. 2025 Jun 24. 1-9

Retinal Microglia: Revealing New Opportunities for Identifying Early Biomarkers of Diabetic Retinopathy.

Ohisa Harley, Yufilia Suci Amelia, Elsa Gustianty, Nanny N M Soetedjo, Arief S Kartasasmita.

   PURPOSE: To explore the role of microglia in the pathomechanism of diabetic retinopathy (DR) from an inflammatory perspective.Methods: The study was conducted by searching several databases. Relevant articles were collected, summarized, and concluded.
RESULTS: Numerous studies have been conducted to identify inflammatory biomarkers for effective detection of DR; however, the results have been inconsistent. Microglia, the resident immune cells of the retinal tissue, are believed to play a potential role in the neuroinflammatory process induced by prolonged hyperglycemia in the retina. The excessive release of extracellular adenosine triphosphate (eATP) due to hyperglycemia may overstimulate P2X7R receptors, thereby activating the NLRP3 inflammasome, and leading to chronic progressive inflammation.
CONCLUSION: Microglial activation and polarization may induce meta-inflammation, contributing to increased permeability and neovascularization, which in turn lead to proliferative diabetic retinopathy. Understanding this mechanism is essential for identifying potential biomarkers for early DR detection and developing adjunctive therapies to control disease progression.

Keywords:  Diabetic retinopathy; Microglia; biomarker; diabetic retinopathy; extracellular adenosine triphosphate; inflammation

DOI:  https://doi.org/10.1080/02713683.2025.2517300
Genes Cells. 2025 Jul;30(4): e70036

Effects of VEGFA and ANGPT2 Antibodies on the Activation of Microglia in the Early Stages of Streptozotocin-Induced Pathogenesis of Diabetic Retinopathy.

Toshiro Iwagawa, Yuta Inokuchi, Kosuke Saita, Tetsuhiro Soeda, Ayumi Usui-Ouchi, Makoto Aihara, Sumiko Watanabe.

  Diabetic retinopathy (DR) is known as a microvascular complication, in which various inflammatory symptoms, including activation of microglia, are observed. A model of hyperglycemia resembling type 1 diabetes mellitus (DM) induced in mice by intraperitoneal injection of streptozotocin (STZ) has been widely used. We examined the effects of anti- vascular endothelial growth factor A (VEGFA) and anti-angiopoietin-2 (ANGPT2) antibodies in addition to a bispecific antibody against VEGFA and ANGPT2 by intravitreously administrated to the eyes on early signs, especially the activation of microglia in STZ-treated mice eyes. After 14 weeks of STZ administration, alterations in activity by ERG and CD31 staining patterns were not observed. Although a difference in the number of microglia in the retina between normal and STZ-model retinas was not observed, the morphology of microglia had changed from ramified in control to amoeboid shape in STZ model at 4 days after the antibodies injection. Detailed morphological examination showed decreases in area, ramification index, and tree length in the STZ-model retinas compared with normal retinas. Recovery from these decreases was demonstrated mainly by the administration of the bispecific antibody. These results suggest that anti-VEGFA/ANGPT2 therapy may suppress the activation of microglia in the early stages of DR.

Keywords:  ANGPT2; VEGFA; diabetes mellitus; microglia; retina

DOI:  https://doi.org/10.1111/gtc.70036