bims-microg 2026-05-31 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–05–31
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.
Maternal-fetal type I interferon signaling drives TREM2 dysregulation and synaptic dysfunction in neurodevelopmental disorders.
TPM1 drives cytoskeleton-immunometabolism coupling and LGALS9/CD45-mediated neuroinflammatory propagation in retinitis pigmentosa.
Curated set of tool compounds to probe PYK2 and FAK signaling in Alzheimer's disease.
Thyroid-stimulating hormone receptor mediates peripheral-central neuroimmune crosstalk in autoimmune thyroid diseases.
The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A ESCRT-mediated lysosomal repair.
PRMT6 inhibition or deficiency attenuates diabetic neuropathic pain in male mice and is associated with reduced spinal neuroinflammation, microgliosis, and altered p53-p21 signaling.
Irisin-integrin αV/β5 coupling of α-synuclein phagocytosis and clearance.
Epigenetic brain reprogramming rejuvenates neuro-immune circuits to reverse Alzheimer's disease pathology and systemic bone loss.
Repeated head impacts establish a senescent cranial bone marrow niche that impairs brain metabolism.
Microglial state transitions dominate the brain immune response in the subacute phase after cardiac arrest.
Microglial Ccl4-Ccr5 signaling links systemic inflammation to synaptic loss and memory deficits in chronic kidney disease.
Integrative genomics and single-cell CRISPRi screening dissect Alzheimer GWAS non-coding variants regulating TSPAN14.
Microglial MARCO facilitates Varicella zoster virus uptake and triggers TLR2-mediated neuroinflammation.
Chronic low-grade hippocampal inflammation blunts exercise-induced neurogenesis and alters the exercise-induced microglia transcriptome in the rat hippocampus.
Platelet factor 4 prevents neuroinflammation and neurodegeneration in Parkinson's disease model via regulating protocadherin gamma/Pyk2 pathway.
RBP4 Aggravates Diabetic Retinopathy by Inducing Microglial Activation and Endothelial Inflammation.
The adenosine A2A receptor antagonist KW6002 mitigates aldosterone-induced central serous chorioretinopathy in mice.
Strain-Dependent Differences in Baseline Retinal Immune Homeostasis: A Comparative Study of Albino and Pigmented Mice.
TREM2 Regulates Microglial Activation via the ERK/p38 Signaling Pathway: Implications for the Pathogenesis of Experimental Autoimmune Uveitis.

Nat Neurosci. 2026 May 26.

Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.

Chensi Liang, Yulan Zhou, Kai Zhuang, Shuzhong Wang, Li Zhong, Dan Can, Aiyu Lei, Huifang Li, Jie Zhang, Lige Leng.

Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and GPNMB, promoting the secretion of EVs containing mitochondria. Functional mitochondria transferred to astrocytes via EVs markedly improve astrocytic functions and attenuate the cognitive impairments and pathogenic features in PS19 mice. By contrast, microglial GPNMB deficiency eliminates mitochondrial EV secretion and mitochondrial transfer to astrocytes, thereby impairing astrocytic functions and exacerbating cognitive impairment in PS19-CcKO (CX3CR1 cre Gpnmb floxp) mice. GPNMB-enriched EVs from PS19 mice alleviate the pathological phenotypes of PS19 mice, offering potential insights for AD treatment.

DOI: https://doi.org/10.1038/s41593-026-02317-w
Neuron. 2026 May 26. pii: S0896-6273(26)00338-7. [Epub ahead of print]

Maternal-fetal type I interferon signaling drives TREM2 dysregulation and synaptic dysfunction in neurodevelopmental disorders.

Matteo Bizzotto, Shih Feng You, Matteo Tamborini, Elisa Faggiani, Raffaella Morini, Antonella Borreca, Rui Zhang, Ekaterina Aladyeva, Aasritha Nallapu, Claudio Ferrari, Oscar Harari, Davide Pozzi, Ricardo D'Oliveira Albanus, Celeste M Karch, Michela Matteoli, Fabia Filipello.

  Maternal infections during gestation cause perturbed neuroimmune interactions and increased risk of neurodevelopmental disorders in the offspring. Using a maternal immune activation model with polyinosinic:polycytidylic acid (poly(I:C)), we investigated how maternal infections reshape the progeny hippocampal landscape. Poly(I:C) increased maternal type I interferon (IFN-I), disrupting neuronal transcriptional trajectories and excitatory synapse homeostasis in juvenile offspring. Poly(I:C) offspring microglia exhibited reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of synapse elimination and brain development, accompanied by impaired phagocytosis and suppressed IFN-I-responsive substate. Consistently, a blunted IFN-I signature was observed in postmortem tissues from schizophrenic patients. TREM2 deficiency was associated with aberrant maternal IFN-I and altered neuronal and microglial signatures in poly(I:C) offspring, highlighting its regulatory role in neurodevelopmental pathologies. Blocking maternal IFN-I signaling restored synaptic defects and TREM2 function, suggesting that monitoring IFN-I responses during pregnancy and targeting defective IFN-I cascades in the newborn may represent viable therapeutic approaches to mitigate neurodevelopmental dysfunctions.

Keywords:  TREM2; brain development; maternal immune activation; microglia; neurodevelopmental disorders; schizophrenia; type I interferon

DOI:  https://doi.org/10.1016/j.neuron.2026.04.043
Sci Adv. 2026 May 29. 12(22): eaea6467

TPM1 drives cytoskeleton-immunometabolism coupling and LGALS9/CD45-mediated neuroinflammatory propagation in retinitis pigmentosa.

Rong Li, Jun-Qi Fan, Bin Lin.

Retinitis pigmentosa (RP), the most prevalent inherited retinal degeneration, features progressive photoreceptor loss with no approved disease-modifying therapies. While microglia-driven neuroinflammation accelerates RP progression, its sustaining mechanisms remain elusive. Through integrated multiomics profiling of retinal degeneration 10 (rd10) mice, we identify tropomyosin 1 (TPM1) as a previously unrecognized cytoskeletal-immune regulator orchestrating spatial neuroinflammation in RP. Genetic ablation of Tpm1 attenuated microglial reactivity and preserved vision, whereas overexpression triggered self-reinforcing inflammation via four interlocked axes: (i) TPM1-mediated activator protein-1 (AP-1) hyperactivation initiates senescence-associated secretory phenotype (SASP) through mitogen-activated protein kinase (MAPK) kinase/extracellular signal-regulated kinase 3-dependent MAPK signaling; (ii) SASP subsequently mediates reduced phagocytosis; (iii) Tpm1-Apoe/Fabp5 axis disruption precipitates lipid droplet accumulation with cholesterol crystallization; (iv) galectin-9 (LGALS9)/CD45-mediated intermicroglial signaling propagates inflammatory signals across the retina. Our work redefines TPM1 as a linchpin in self-sustaining neurodegeneration cycles, where cytoskeletal dysfunction fuels immunometabolic collapse. These findings unveil precision therapeutic strategies targeting TPM1 hubs-notably the LGALS9/CD45 axis-to disrupt inflammatory cycles while preserving retinal homeostasis.

DOI: https://doi.org/10.1126/sciadv.aea6467
Alzheimers Dement. 2026 May;22(5): e71508

Curated set of tool compounds to probe PYK2 and FAK signaling in Alzheimer's disease.

Pathum M Weerawarna, Cynthia D Jesudason, Karen L Lobb, Emily R Mason, Xiaoping Gu, Shaoyou Chu, Timothy I Richardson.

   INTRODUCTION: Proline-rich tyrosine kinase 2 (PYK2) and focal adhesion kinase (FAK) are non-receptor tyrosine kinases implicated in Alzheimer's disease (AD), but their functional role in microglia remains understudied. Selective pharmacological tools are required for preclinical studies leading to translational therapeutic development.
METHODS: We evaluated potent and selective inhibitors described in publications and patents, synthesized or procured representative compounds, and profiled them in kinase assays. In vitro physicochemical and pharmacokinetic (PK) properties were assessed, and functional effects were studied in microglial phagocytosis assays using HMC3 and BV2 microglia cellular models.
RESULTS: Biochemical profiling confirmed potent and selective inhibition, consistent with reported data, though assay-dependent differences in apparent selectivity were observed. Most compounds showed favorable physicochemical and PK properties. In HMC3 assay, the PYK2-selective tool compounds showed that strong stimulation of phagocytosis and parallel cell counts declined at non-toxic concentrations.
DISCUSSION: This curated set of well-characterized inhibitors provides a validated toolkit to probe PYK2/FAK biology in AD-relevant models.

Keywords:  Alzheimer's disease; FAK; PYK2; drug discovery; focal adhesion kinase; proline‐rich tyrosine kinase 2; tool compounds

DOI:  https://doi.org/10.1002/alz.71508
BMC Med. 2026 May 27.

Thyroid-stimulating hormone receptor mediates peripheral-central neuroimmune crosstalk in autoimmune thyroid diseases.

Haiyang Zhang, Shufan Jiang, Tianyi Zhu, Yuting Liu, Jipeng Li, Sijie Fang, Yinwei Li, Jing Sun, Xinheng He, Chuanjun Tong, Zhengrun Gao, Xianqun Fan, Huifang Zhou.

   BACKGROUND: Organ-specific autoimmune diseases, particularly Graves' disease (GD) and its extrathyroidal manifestation, Graves' orbitopathy (GO), are characterized by systemic autoimmunity that may extend its impact to the central nervous system (CNS). While thyroid-stimulating hormone receptor (TSHR) is the primary driver of pathological remodeling in the thyroid and orbital tissues, emerging evidence suggests it is also expressed in the brain and may participate in neuroimmune signaling. However, the molecular mechanisms linking peripheral TSHR-driven autoimmunity to these extended systemic features remain unclear. Thus, GD and GO provide a unique window to investigate how peripheral autoantibodies influence CNS involvement as part of its broader pathological spectrum.
METHODS: Genome-wide association studies (GWAS) and post-GWAS analyses were integrated with bulk RNA sequencing, single-cell and spatial transcriptomics, and brain imaging phenotypes to comprehensively characterize peripheral and central alterations in GD and GO. Mendelian randomization was applied to test causal relationships between genetic variants and brain signatures. Structural biology analyses were further conducted including protein-protein docking, small-molecule docking, and normal mode dynamics to identify prospective modulators of TSHR. Immunofluorescence staining was performed in a GO mouse model to validate the colocalization of potential interacted proteins in the specific brain region.
RESULTS: Brain imaging-derived phenotypes (IDPs) alterations in GO and GO were systematically analyzed to identify neuroanatomical and functional alterations. TSHR was further identified as a shared genetic driver across peripheral and central compartments. TSHR was expressed in spiny projection neurons, microglia, and peripheral T cells, with cell-cell communication analyses highlighting TSHR-mediated interactions among neurons, endothelial cells, and microglia. Immunofluorescence staining in a GO mouse model confirmed the colocalization of TSHR with FN1 and GNAS in the basal ganglia, providing tissue-level validation of the computationally predicted ligand-receptor interactions. Immune profiling further showed immune alterations in GD and GO. Structural modeling supported plausible physical interfaces between TSHR and interacting proteins, and small-molecule screening identified three repurposable compounds - venetoclax, irinotecan, and dutasteride - with predicted favorable docking scores and stable binding poses in our simulations.
CONCLUSIONS: These findings demonstrate that TSHR acts as a molecular hub mediating peripheral-central neuroimmune crosstalk in GD and GO. The results support a broader "disease-molecule axis" framework that links genetic susceptibility with multi-level immune and neural mechanisms. This work provides mechanistic insights relevant to the development of TSHR-targeted therapies, with implications for both peripheral immune modulation and central regulation. However, the limited sample size, lack of longitudinal follow-up, and absence of in vivo validation warrant cautious interpretation and further investigation.

Keywords:  Graves’ disease; Graves’ orbitopathy; genome-wide association studies; multi-omics; resting-state functional magnetic resonance imaging; thyroid-stimulating hormone receptor

DOI:  https://doi.org/10.1186/s12916-026-04957-y
EMBO J. 2026 May 29.

The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A ESCRT-mediated lysosomal repair.

Shan Li, Shidong Xu, Feng Li, Qirui Zhao, Penghui Zhang, Qinghua Guan, Xiangxiang Sun, Jundong Bi, Hu Xiao, Yiyuli Tang, Cheng Peng, Qingfeng Chen, Yonghua Wang, Mei Yang.

Microglia are critical regulators of neuroinflammation and neurodegeneration. Haploinsufficiency of C9orf72, the most frequently mutated gene in amyotrophic lateral sclerosis and frontotemporal dementia, has been linked to autophagy-lysosomal pathway defects, but the role of C9orf72 in microglia remains unclear. Here, we identify the C9orf72/SMCR8 complex as a key regulator of microglial homeostasis through promoting lysosomal membrane repair. Loss of C9orf72 and SMCR8 in mice causes age‑dependent neuroinflammation and microgliosis, with microglia adopting a disease-associated state. In aged brain and spinal cord tissue, microglia display lysosomal damage marked by galectin‑3 accumulation. Using a lysosomotropic agent to induce lysosomal damage in microglia, we find that C9orf72/SMCR8-deficient cells accumulate damaged lysosomes and show defective recruitment of phosphorylated RAB8A and the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery to damaged lysosomes. Notably, mutant microglia accumulate GTP‑bound RAB8A, which becomes hyperphosphorylated and mislocalized to RAB7-positive, LAMP1-negative vesicles. The GTPase-activating activity of the C9orf72/SMCR8 complex is essential for lysosomal repair. Our findings reveal that the C9orf72/SMCR8 complex coordinates RAB8A-ESCRT-mediated lysosomal repair to safeguard microglial homeostasis and limit neuroinflammation.

DOI: https://doi.org/10.1038/s44318-026-00817-w
J Neuroinflammation. 2026 May 29.

PRMT6 inhibition or deficiency attenuates diabetic neuropathic pain in male mice and is associated with reduced spinal neuroinflammation, microgliosis, and altered p53-p21 signaling.

Yan Chu, Honghao Song, Mengqiu Deng, Yuanyuan Fang, Ruifeng Ding, Kesheng Huang, Xiaoyi Fan, Lei Peng, Yutong Yang, Huawei Wei, Chaofeng Han, Hongbin Yuan.

  Diabetic neuropathic pain (DNP) is a major contributor to chronic pain in adults, yet effective targeted therapies are still lacking, underscoring the need to elucidate its underlying mechanisms. Microglial proliferation and activation are key drivers of central sensitization and pain hypersensitivity. In a type 2 diabetes mouse model, protein arginine methyltransferase 6 (PRMT6) was markedly upregulated in spinal dorsal horn microglia in male mice, and high-glucose stimulation similarly increased PRMT6 expression in BV-2 cells, accompanied by enhanced proliferation and inflammatory activation. Genetic deletion of Prmt6 or pharmacological inhibition with EPZ020411 alleviated pain hypersensitivity and reduced spinal microgliosis and inflammation in male mice. Transcriptomic analysis revealed enrichment in cell proliferation-related processes and the p53 signaling pathway. In BV-2 cells, PRMT6 knockdown induced G0/G1 arrest and attenuated high-glucose-induced proliferation and inflammatory activation, whereas PRMT6 overexpression exerted opposite effects. Mechanistically, PRMT6 methylated p53 and decreased its transcriptional activity, leading to reduced p21 mRNA expression and enhanced cell-cycle progression. In contrast, in female DNP mice, spinal microgliosis was limited, PRMT6 expression remained unchanged, and Prmt6 deficiency did not significantly alter spinal microglial density, inflammatory markers, or nociceptive hypersensitivity. Collectively, our results uncover a previously unrecognized PRMT6-p53-p21 regulatory axis that may contribute to microglial proliferation and neuroinflammation under hyperglycemic conditions in male mice, highlighting PRMT6 as a potential therapeutic target for microglia-associated DNP.

Keywords:  Cell cycle; Diabetic neuropathic pain; Microglial proliferation; PRMT6; p21; p53

DOI:  https://doi.org/10.1186/s12974-026-03893-1
J Neuroinflammation. 2026 May 26.

Irisin-integrin αV/β5 coupling of α-synuclein phagocytosis and clearance.

Yihan Liu, Shijie Shi, Jingyuan Zhang, Mengyao Huang, Mengxue Wang, Tingting Zhang, Wei Wang, Jie Xiang.

  Parkinson's disease-associated cognitive impairment (PD-CI) is closely linked to α-synuclein (α-syn) accumulation and synaptic dysfunction, yet effective disease-modifying strategies remain limited. Irisin is an exercise-inducible myokine with neuroprotective potential, but its receptor mechanisms and its role in α-syn clearance in PD-CI are poorly defined. Here, we observed that aerobic exercise markedly increased circulating irisin levels, reduced serum α-syn levels, and improved cognitive performance in a cohort of 21 PD patients. In addition, irisin signals through integrin αV/β5 to enhance microglial α-syn clearance, resulting in reduced α-syn burden and improved PD-CI. Mechanistically, irisin activates integrin αV/β5-FAK axis to promotes microglial phagocytic uptake of α-syn, while concurrently stabilizing HMGB1 to facilitate autophagy-lysosome mediated degradation of internalized α-syn, thereby coupling phagocytic uptake to efficient degradation. In summary, these results highlight a dual-module irisin-integrin αV/β5 mechanism that couples microglial phagocytosis and autophagy-lysosome clearance to reduce α-syn burden and ameliorate PD-CI.

Keywords:  Clearance; Integrin αV/β5; Irisin; Phagocytosis; α-synuclein

DOI:  https://doi.org/10.1186/s12974-026-03882-4
J Neuroinflammation. 2026 May 28.

Epigenetic brain reprogramming rejuvenates neuro-immune circuits to reverse Alzheimer's disease pathology and systemic bone loss.

Mei-Dan Wan, Xi-Xi Liu, Teng-Fei Wan, Yi-Wei Liu, Ya-Ling Jiang, Jing-Tao Zou, Bin Jiao, Qian-Qian Liu, Ling Jin, Ran Duan, Zun Wang, Chun-Gu Hong, Xin Wang, Xin-Yue Hu, Xin-Xin Liao, Jia Cao, Lu Shen, Hui Xie, Zhen-Xing Wang.

  Alzheimer's disease (AD) is characterized by progressive neurodegeneration, neuroinflammation, and systemic comorbidities, yet disease-modifying therapies remain elusive. Here, we show that partial epigenetic reprogramming via brain-restricted expression of Oct4, Sox2, and Klf4 (OSK) restores neuronal and neuroimmune homeostasis without loss of cellular identity. In APP/PS1 mice, OSK reprogramming improves cognitive performance across disease stages, reduces amyloid-β deposition, attenuates microglial activation, preserves synaptic integrity, and limits neuronal apoptosis. Mechanistically, reduced representation bisulfite sequencing reveals widespread reversal of AD-associated DNA methylation patterns, which is dependent on Tet2-mediated demethylation, establishing epigenetic rejuvenation as a key driver of functional recovery. Unexpectedly, brain-restricted OSK reprogramming also ameliorates systemic bone loss by reshaping brain-derived extracellular vesicle signaling, including modulation of miR-483-5p, thereby restoring osteogenic capacity. Together, these findings identify partial epigenetic reprogramming as a strategy to rewire neuro-immune circuits and link central nervous system rejuvenation to peripheral tissue homeostasis, providing a conceptual framework for targeting both neurodegeneration and its systemic consequences in AD.

Keywords:  Alzheimer's disease; Bone loss; Demethylation; Microglia; Neuron; OSK; Reprogramming

DOI:  https://doi.org/10.1186/s12974-026-03854-8
J Neuroinflammation. 2026 May 27.

Repeated head impacts establish a senescent cranial bone marrow niche that impairs brain metabolism.

Patrick J Devlin, Romeesa Khan, Trang H Do, Bryce E West, Janelle M Korf, Gary U Guzman, John Ahn, Alexander Saltzman, Antrix Jain, Chunfeng Tan, Rene Flores, Micheal E Maniskas, Sean P Marrelli, Anna Malovannaya, Erica Underwood, Rodney M Ritzel.

   BACKGROUND: Traumatic brain injury (TBI) of any severity is associated with long-term systemic inflammation and increased risk of peripheral comorbidities, yet the mechanisms driving immune dysregulation and accelerated aging after repeated sub-concussive head impacts remain poorly defined. Here, we investigated the acute and chronic effects of repetitive head impacts (RHI) on distal and proximal bone marrow compartments in the femur and calvaria, respectively.
METHODS: Using a modified weight-drop mouse model delivering rotational and acceleration-deceleration forces (3 hits/week for up to 16 weeks), RHI produced no mortality, skull fracture, hemorrhage, or brain leukocyte infiltration. Bone marrow stem and progenitor cell proliferation, senescence, and output were assessed using flow cytometry, senescence-associated assays, telomere analysis, and secretome profiling.
RESULTS: One day after three consecutive impacts, RHI induced robust proliferation of LSK stem/progenitor cells in both femoral and calvarial marrow, evidenced by Ki67 expression, BrdU incorporation, and increased monocyte output. By 8 weeks (24 impacts), injury-induced proliferation subsided and LSK cells exhibited increased senescence-associated β-galactosidase activity and upregulation of tumor suppressor genes. At 16 weeks (48 impacts), LSK populations were depleted at both sites, displaying reduced proliferative capacity, telomere shortening, and pancytopenia in otherwise young adult mice. Calvarial bone marrow cells exposed to RHI released a distinct cytokine and proteomic secretome marked by elevated IL-6, suppressed mitochondrial and metabolic signaling, and enhanced DNA repair pathways. Notably, skull-derived secretome factors impaired cortical and hippocampal mitochondrial metabolism, and reduced microglial mitochondrial membrane potential.
CONCLUSIONS: Together, these findings identify replicative senescence of the brain-adjacent bone marrow niche as an early and progressive consequence of repeated mild head injury, linking RHI to long-lasting metabolic dysfunction, impaired immunity, and accelerated aging.

Keywords:  Metabolism; Microglia; Repetitive head impacts; Replicative senescence; Skull bone marrow; Traumatic brain injury

DOI:  https://doi.org/10.1186/s12974-026-03846-8
J Neuroinflammation. 2026 May 27.

Microglial state transitions dominate the brain immune response in the subacute phase after cardiac arrest.

Lihong Dang, Ran Zhang, Jin Zhang, Peibang He, Xinyuan Yu, Ata Ur Rehman, Ángela Del Águila, Vaibhav Jain, Jilin Tian, Emily Xu, Huaxin Sheng, Wei Yang.

  Cardiac arrest (CA) is a life-threatening medical emergency, and most victims are elderly. Despite advances in resuscitation, post-CA morbidity and mortality remain high, and this is thought to result largely from brain injury in which neuroinflammation plays a key role. Yet, how individual immune cell populations contribute to the immune response in the post-CA brain is still poorly understood. Here, using single-cell RNA-sequencing (scRNA-seq), we revealed the first immune landscape of the young and aged brain on day 3 after CA. Our data demonstrate that transitions in microglial states constituted a dominant immune change in the post-CA brain. We identified 5 CA-associated microglial states that included 3 major clusters defined by pro-inflammatory signatures, a proliferative phenotype, and high Spp1 expression. These 3 states exhibited age-dependent differences: the inflammatory subset was markedly expanded in aged mice, whereas the proliferative and Spp1⁺ clusters were more prominent in young mice. Such divergent responses likely underpin age-related disparities in neurologic outcome after CA. Notably, Spp1+ microglia displayed unique spatiotemporal dynamics. These cells were robustly induced by CA, and were enriched in selective brain regions including the basal ganglia where they were associated with a microinfarct-like injury pattern. Lastly, we found that microglial depletion worsened functional outcome after CA, suggesting an overall protective role for microglia. Together, these findings provide novel insights into microglial heterogeneity and age-dependent immune responses in the brain after CA, and highlight the central role of microglia in shaping post-CA recovery.

Keywords:  OPN; PLX3397; aging; basal ganglia; globus pallidus; proliferation

DOI:  https://doi.org/10.1186/s12974-026-03874-4
J Neuroinflammation. 2026 May 25.

Microglial Ccl4-Ccr5 signaling links systemic inflammation to synaptic loss and memory deficits in chronic kidney disease.

Yaochen Cao, Jingyun Wang, Xitong Li, Xin Chen, Jinsheng Xiong, Tianyao Wang, Hongming Sun, Ziqiang Wang.

   BACKGROUND: Chronic kidney disease (CKD) is increasingly associated with cognitive impairment, yet the molecular pathways connecting systemic inflammation to synaptic dysfunction remain unclear. This study investigates the role of the Ccl4-Ccr5 axis in microglia-mediated synaptic phagocytosis during CKD-associated cognitive decline.
METHODS: A 5/6 nephrectomy rat model was established in rats to induce CKD, validated by renal function markers. Cognitive performance was evaluated through spatial, contextual, and recognition memory tests. Hippocampal cellular alterations were analyzed using single-cell RNA sequencing and immunofluorescence for microglial activation and synaptic density. The functional roles of Ccr5 were assessed via in vivo and in vitro CRISPR-mediated knockdown or overexpression, while Ccl4-Ccr5 interactions were confirmed by co-immunoprecipitation.
RESULTS: CKD rats showed significant cognitive deficits, increased hippocampal microgliosis, and synaptic loss. Ccr5 knockdown reduced microglial synaptic engulfment, restored synaptic plasticity, and improved memory, whereas Ccr5 overexpression enhanced phagocytic activity.
CONCLUSIONS: These findings demonstrate that Ccl4-Ccr5 signaling drives pathological synaptic elimination by microglia, linking systemic inflammation to cognitive decline in CKD. Targeting this pathway may provide a therapeutic approach to preserve neuronal function.

Keywords:  Ccl4-Ccr5 axis; Chronic kidney disease; Cognitive impairment; Microglia; Neuroinflammation; Synaptic phagocytosis

DOI:  https://doi.org/10.1186/s12974-026-03852-w
Am J Hum Genet. 2026 May 26. pii: S0002-9297(26)00161-8. [Epub ahead of print]

Integrative genomics and single-cell CRISPRi screening dissect Alzheimer GWAS non-coding variants regulating TSPAN14.

Shannon Laub, Natalia Tulina, Matthew Hoffman, Joe Bormeh Faryean, Sandhya Ramachandran, Khanh Trang, Stephanie M Lewkiewicz, Alessandra Chesi.

  Genome-wide association studies (GWASs) have uncovered many associations for human complex diseases, but functional dissection of the discovered loci has lagged behind. We present a variant-to-gene (V2G) mapping effort for Alzheimer disease (AD) leveraging the most recent AD GWAS meta-analyses. In this study, we integrated ten brain-relevant genomics datasets-including promoter Capture C, ATAC-seq, and RNA-seq from microglia, neurons, and astrocytes-to fine-map AD GWAS variants and identify effector genes. We then performed a single-cell CRISPRi Perturb-seq screen targeting 74 candidate regulatory regions in the human microglial cell line HMC3. Our V2G mapping effort identified 93 candidate causal variants and 94 effector genes (72 coding) for 35 AD loci. Our CRISPRi screen across ∼97,000 cells validated 21 variant-gene pairs. We showed that an intronic region at the TSPAN14 locus containing rs7080009, rs1870138, and rs1870137 is a microglial-specific enhancer activated by the AD-risk haplotype. CRISPR-mediated deletion of this region reduced TSPAN14 expression, disrupted cell-adhesion pathways, and lowered secretion of pro-inflammatory cytokines interleukin 6 (IL-6) and IL-8. Our study provides a systematic framework for mapping GWAS signals to effector genes in a cell-type-specific manner and identifies robust leads for in-depth functional investigations.

Keywords:  Alzheimer disease; GWAS; Perturb-seq; TSPAN14; enhancer regulation; functional genomics; microglia; non-coding variants; single-cell CRISPRi screen; variant-to-gene mapping

DOI:  https://doi.org/10.1016/j.ajhg.2026.04.011
J Biomed Sci. 2026 May 23. pii: 53. [Epub ahead of print]33(1):

Microglial MARCO facilitates Varicella zoster virus uptake and triggers TLR2-mediated neuroinflammation.

Ji-Soo Lim, Soo-Jin Oh, Ji-Yeun Hur, Subin Oh, Seuk-Min Ryu, Rafael T Han, Hosun Park, Dawn M E Bowdish, Ok Sarah Shin.

   BACKGROUND: Varicella zoster virus (VZV) is a human neurotropic virus that can establish latency in sensory neurons. Microglia play a complex role during neurotropic virus infections; however, their role during VZV infection remains to be determined. In the present study, we explored the role of VZV-induced alterations in the morphodynamics and function of microglia in triggering neuroinflammation.
METHODS: We prepared cell-free VZV and compared replication efficiencies of wild-type (YC01) and attenuated (MAV/06, MAV) VZV in two transformed human microglial cell lines (HMC3 and HIM) and human embryonic stem cell (ESC)-derived microglia (ESC-MG). Bulk RNA sequencing was used to assess molecular signatures of microglia following VZV infection in ESC-MG, and cytokine profiles were determined to further investigate neuroinflammation. To further examine the impact of VZV-induced microglial inflammation on neuronal responses, we generated ESC-derived sensory neurons (ESC-SN) and evaluated nociceptor expression and calcium flux as a readout for SN activities following microglial secretome treatment.
RESULTS: VZV upregulates its gene and protein expression and triggered morphological changes in various microglia cultures. Transcriptomic analysis of YC01-infected ESC-MG revealed a robust induction of genes associated with antiviral innate immunity, alongside a pronounced upregulation of macrophage receptor with collagenous structure (MARCO). Functional studies demonstrated that MARCO facilitates VZV uptake in microglia by binding to the viral glycoprotein E (gE) via its C-terminal scavenger receptor cysteine-rich (SRCR) domain, thereby promoting viral entry and phagocytosis. Moreover, VZV infection elicited neuroinflammation in an ORF62-dependent manner, while MARCO activation triggered toll-like receptor 2 (TLR2)-mediated inflammatory signaling. This cascade further amplified the expression of pain-associated molecular mediators in an ESC-SN model, highlighting a potential mechanistic link between microglial MARCO and VZV-triggered neuropathic processes.
CONCLUSION: Our results show, for the first time, that microglia are susceptible to VZV infection and identify MARCO as an important mediator for regulating TLR2-mediated neuroinflammation and promoting an upregulation of factors associated with neuropathic pain.

Keywords:  MARCO; Microglia; Sensory neurons; TLR2; Varicella zoster virus

DOI:  https://doi.org/10.1186/s12929-026-01256-9
Brain Behav Immun. 2026 May 23. pii: S0889-1591(26)00563-5. [Epub ahead of print]137 106815

Chronic low-grade hippocampal inflammation blunts exercise-induced neurogenesis and alters the exercise-induced microglia transcriptome in the rat hippocampus.

Sarah Nicolas, Maria Giovanna Caruso, Sebastian Dohm-Hansen, Tara Foley, Paul J Lucassen, Joram D Mul, Aonghus Lavelle, Jane A English, Olivia F O'Leary, Yvonne M Nolan.

  Chronic low-grade neuroinflammation contributes to inflammageing by compromising hippocampal plasticity, with interleukin-1β (IL-1β) as a key mediator. The extent to which sustained hippocampal inflammation can interfere with the potential beneficial effects of exercise on plasticity and hippocampus-related behaviour remains unclear. Here we combined bilateral hippocampal IL-1β overexpression (IL-1β-OE), to mimic chronic low-grade neuroinflammation with voluntary wheel running, to mimic human exercise training, in adult male Sprague-Dawley rats. We assessed effects on multiple dorsal hippocampal-related behaviours, adult hippocampal neurogenesis, microglial reactivity, and immune cell infiltration. Hippocampal IL-1β-OE impaired pattern separation, independent of exercise training, and attenuated exercise-induced increases in neurogenesis in the dorsal hippocampus. Hippocampal IL-1β-OE promoted microglial lipid-droplet accumulation, which exercise paradoxically exacerbated. Transcriptomic profiling revealed that exercise in combination with hippocampal IL-1β-OE enriched immune and leukocyte trafficking pathways in microglia, while hippocampal IL-1β-OE alone increased hippocampal CD8+ T cell infiltration. These findings indicate that chronic hippocampal inflammation alters microglial and neurogenic responses to exercise, suggesting that inflammatory status critically influences exercise efficacy in supporting hippocampal plasticity.

Keywords:  Behaviour; Chronic Neuro inflammation; Exercise; Hippo campal neurogenesis; Hippocampus; IL-1β; Microglia

DOI:  https://doi.org/10.1016/j.bbi.2026.106815
Brain Behav Immun. 2026 May 25. pii: S0889-1591(26)00580-5. [Epub ahead of print]137 106832

Platelet factor 4 prevents neuroinflammation and neurodegeneration in Parkinson's disease model via regulating protocadherin gamma/Pyk2 pathway.

Pinyuan Huang, Xuan Liu, Ruohan Yang, Yaoyi Zhang, Qinyong Ye, Nan Lin, En Huang.

  Recent studies have reported that platelet factor 4 (PF4), also known as platelet-derived exokine CXCL4, is a critical factor in rejuvenating brain ageing and cognitive impairment by attenuating neuroinflammation. Our transcriptomic analysis indicated that 3 protocadherin gamma (Pcdhg) members (Pcdhga10, Pcdhgb4, and Pcdhgb5) were prominently upregulated by PF4 overexpression. This study aims to investigate whether PF4 plays a protective role in the pathogenesis of Parkinson's disease models and explore its underlying molecular mechanism by regulating Pcdhg and its downstream Pyk2. Pcdhg interacts and blocks Pyk2 autophosphorylation (p-Pyk2) and activation. Present study indicated that MPTP treatment decreased Pcdhg while increased p-Pyk2, p-NF-kB, IL-1β, TNF, and phosphorylated-synuclein in Substantia nigra pars compacta (SNc). Both systemic administration of PF4 via the tail vein and local overexpression of lentiviral PF4 administration increased Pcdhg, decreased p-Pyk2, p-NF-kB, IL-1β, TNF, and p-synuclein. PF4 also ameliorated the compromised behavioral activity, neuroinflammation, and neurodegeneration in MPTP injected mice PD model. This study also showed that Pcdhg induced by PF4 was mainly expressed in microglia, whereas Pyk2 was expressed in neurons and microglia. Pcdhg was a transmembrane cell adhesion molecule and microglial Pcdhg may contact neurons through extracellular matrix and activate neuronal Pyk2 activation. This study also showed that Pcdhg induced by PF4 was mainly expressed in microglia, whereas Pyk2 was expressed in neurons and microglia. Pcdhg was a transmembrane cell adhesion molecule and microglial Pcdhg may contact neurons through extracellular matrix and activate neuronal Pyk2 activation. Pyk2 inhibitor PF-562271 administration decreased Pyk2, restored the compromised behavioral activity, neuroinflammation, and dopaminergic cell death in MPTP-injected mice. This study demonstrates that blood-borne PF4 prevents neuroinflammation and neurodegeneration in PD models by inducing Pcdhg expression and subsequently blocking Pyk2 activation. This finding highlights that Pcdhg/Pyk2 axis was a key protective molecular mechanism of PF4 in PD and the Pcdhg-Pyk2 pathway could serve as a potential drug target for PD interventions.

Keywords:  Neuro inflammation; Parkinson’s disease; Platelet Factor 4; Protocadherin gamma; Pyk2

DOI:  https://doi.org/10.1016/j.bbi.2026.106832
Diabetes. 2026 May 28. pii: db250816. [Epub ahead of print]

RBP4 Aggravates Diabetic Retinopathy by Inducing Microglial Activation and Endothelial Inflammation.

Ying Shi, Congjuan Mao, Di Zhang, Yanfang Zhu, Yi Lei, Xue Dong, Mengyu Liao, Mei Du.

ARTICLE HIGHLIGHTS: Retinol-binding protein 4 (RBP4) levels are elevated in the vitreous humor of patients with diabetic retinopathy (DR) and in RBP4 transgenic mice. Elevated vitreous RBP4 exacerbates both vascular and neuronal deficits associated with DR in streptozotocin-induced diabetic mice. Hyperglycemia augments the RBP4-induced inflammatory response in retinal microvascular endothelial cells to exacerbate DR-related vascular pathologies. RBP4 triggers retinal microglial activation and phagocytosis via TLR4/nuclear factor-κB/mitogen-activated protein kinase pathway, and microglial depletion or inhibition alleviates RBP4-induced retinal neurodegeneration.

DOI: https://doi.org/10.2337/db25-0816
Neuropharmacology. 2026 May 22. pii: S0028-3908(26)00209-1. [Epub ahead of print]297 111036

The adenosine A2A receptor antagonist KW6002 mitigates aldosterone-induced central serous chorioretinopathy in mice.

Qiaoli Liu, Zijun Yu, Wei-Hang Tang, Jiasheng Yang, Jia-Nan Que, Jiaqi Li, Kailang Xu, Jia Qu, Jiang-Fan Chen.

   PURPOSE: Central serous chorioretinopathy (CSC), a prevalent disease characterized by choroidal vascular abnormalities, has extremely limited treatment options. This study investigates the effects of the selective adenosine A2A receptor (A2AR) antagonist KW6002 on choroidal vascular hyperpermeability and the blood-retinal barrier (BRB), and explores its therapeutic potential in experimental CSC.
METHODS: We examined A2AR expression in the retinal pigment epithelium (RPE)-choroid-sclera complex using quantitative real-time PCR (qPCR) and Western blotting (WB) in mice with an established aldosterone-induced acute CSC model. Before modeling and after model establishment, mice were administered 5 mg/kg KW6002 or a vehicle control via intraperitoneal injection. The retinal and choroidal thickness was assessed by optical coherence tomography (OCT) and hematoxylin-eosin (H&E) staining. We observed Müller cells activation, retinal microglia infiltration, and proinflammatory cytokine expression via immunofluorescence and qPCR. Next, we employed the effects of the A2AR antagonist KW6002 and genetic A2AR knockout (A2AR-KO) on BRB integrity using immunofluorescence and WB. Finally, to clarify how A2AR knockout confers therapeutic benefits in CSC, we assessed activation of the TNF-α/NF-κB-MMP-2/9 signaling pathway.
RESULTS: We found that A2AR signaling was significantly upregulated in the RPE-choroid-sclera complex in CSC models, and both A2AR antagonist KW6002 and A2AR-KO significantly inhibited the aldosterone-induced central retinal and choroidal pathologic thickening. Moreover, the KW6002 intervention decreased the activation of Müller cells and the proliferation of microglia, inhibited the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), and ameliorated the retinal damage caused by aldosterone; in contrast, A2AR-KO resulted in significant upregulation of key tight junction proteins (ZO-1, Claudin-1, and Claudin-5). In summary, these results suggest that the protective effects may be correlated with the suppression of the TNF-α/NF-κB-MMP-2/9 signaling axis.
CONCLUSIONS: Our findings show that the A2AR antagonist KW6002 or A2AR-KO offers a protective effect in experimental CSC, reduces inflammation, and maintains the integrity of the BRB, which may be associated with the inhibition of the TNF-α/NF-κB-MMP-2/9 pathway. These findings present a new method for preventing and treating CSC, which will guide our future clinical strategy development.

Keywords:  Adenosine A(2A) receptor; Blood-retinal barrier; Central serous chorioretinopathy; Inflammation; TNF-α/NF-κB-MMP-2/9 signaling pathway

DOI:  https://doi.org/10.1016/j.neuropharm.2026.111036
Cell Mol Neurobiol. 2026 May 29.

Strain-Dependent Differences in Baseline Retinal Immune Homeostasis: A Comparative Study of Albino and Pigmented Mice.

Miguel A Martínez-López, Víctor Paleo-García, Sara Rubio-Casado, José A Fernández-Albarral, José A Matamoros, Juan J Salazar, Ana I Ramírez, Eva M Marco, Meritxell López-Gallardo.

  Mouse models are essential for glaucoma research; however, strain-dependent biological differences may complicate the interpretation and translational value of experimental findings. Because baseline retinal immune tone can shape the response to ocular hypertension (OHT), defining constitutive inflammatory profiles across commonly used mouse strains is critical. Basal intraocular pressure (IOP), retinal interleukin (IL)-1β, interferon gamma (IFN-γ), IL-6, IL-4, IL-10, and vascular endothelial growth factor (VEGF) levels by Luminex xMAP, and the cellular localization of inflammatory mediators by immunofluorescence using Iba-1, GFAP, Brn3a, NF-200, and VEGFR1 were compared between male albino Swiss CD1 and pigmented C57BL/6J mice. Basal IOP did not differ between strains, whereas the basal retinal immune environment did. CD1 mice showed higher IL-1β and IL-4 levels and detectable IFN-γ, whereas C57BL/6J mice showed higher IL-6, IL-10, and VEGF levels. Immunofluorescence revealed strain-specific localization: in CD1 retinas, IL-1β was detected in microglia and macroglia, IFN-γ in microglia, and IL-6 mainly in microglia; in C57BL/6J retinas, IL-1β and IL-6 were mainly associated with macroglia (Müller cells and astrocytes), and IL-4 with microglia. In both strains, IL-10 localized to NF-200-positive axons and VEGFR1 to glial fibrillary acidic protein (GFAP)-positive macroglia. Despite similar basal IOP, albino Swiss CD1 and pigmented C57BL/6J mice differ markedly in their basal retinal immune profiles. Albino mice show a more reactive baseline state, whereas pigmented mice display tighter immunoregulation and stronger immune-vascular support. Strain selection is therefore critical for experimental design, data interpretation, and translational relevance to ensure preclinical findings translate into human outcomes.

Keywords:  Albino CD1 mice; Macroglial cells; Microglial cells; Pigmented C57BL/6J mice; Retina; Retinal ganglion cells (RGCs)

DOI:  https://doi.org/10.1007/s10571-026-01755-1
Invest Ophthalmol Vis Sci. 2026 May 01. 67(5): 67

TREM2 Regulates Microglial Activation via the ERK/p38 Signaling Pathway: Implications for the Pathogenesis of Experimental Autoimmune Uveitis.

Yang Yu, Xuemei Su, Zihao Zhuang, Pengcheng Hu, Mingjia Wang, Zhikang Liao, Peizeng Yang, Jianmin Hu.

Purpose: The purpose of this study was to investigate the role of the trigger receptor expressed on myeloid cell 2 (TREM2) in experimental autoimmune uveitis (EAU) and elucidate the mechanisms by which TREM2 modulated inflammation and microglial activation via key signaling pathways.
Methods: EAU mouse models and microglial cell BV2 inflammation models were established to explore TREM2 function. TREM2 expression in EAU retinas was detected using public databases and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RT-qPCR, Western blotting, enzyme-linked immunosorbent assay (ELISA), and flow cytometry assessed TREM2 functional phenotypes in autoimmune uveitis. Western blotting and RNA sequencing (RNA-seq) analyzed key signaling pathways' activation to clarify TREM2's molecular mechanisms of inflammatory regulation.
Results: TREM2 expression in EAU was elevated at inflammatory peak and reduced during resolution. TREM2 knockdown in inflamed microglia exacerbated inflammation, whereas overexpression alleviated it. TREM2 knockout in EAU mice enhanced retinal vascular leakage, elevated splenic Th1 and Th17 cell proportions, and reduced Treg cell proportions. TREM2 knockdown promoted phosphorylated ERK/p38 activation; overexpression suppressed it. RNA-seq revealed altered retinal mRNA profiles in TREM2 knockout EAU mice, with activation of ERK/p38-associated pathways including the mitogen-activated protein kinase (MAPK) pathway.
Conclusions: TREM2 exerted an anti-inflammatory role in EAU pathogenesis, likely by regulating microglial activation and inhibiting the ERK/p38 signaling pathway in these cells.

DOI: https://doi.org/10.1167/iovs.67.5.67