bims-microg 2026-07-26 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–07–26
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Disease-associated microglia adopt stage-specific phenotypes that regulate T cell fate and immunity in glioma.
Small Extracellular Vesicles From Cardiomyocytes Activate Microglia Aggravating HFpEF.
Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies.
Human Dental Pulp Stem Cell Secretome Restores Ischemic Stroke-Impaired Motor and Cognitive Functions by Reprogramming Redox and Inflammatory Signaling.
Identifying a Csmd3+ Microglial Subpopulation that Drives Cold-to-Hot Transition and Immune-Cure in Glioblastoma.
Photobiomodulation of immune crosstalk rescues neuroinflammation in Alzheimer's disease models.
Programmable microfluidic modeling of the glioblastoma immune microenvironment recapitulates temporally regulated tumor-immune signaling.
Complement dysregulation during the early phases of synucleinopathy.
PLIN2-PGAM5-regulated lipid droplet-mitochondria contacts drive microglial neuroinflammation after spinal cord injury via fatty acid metabolic reprogramming.
Microglia functions in peripheral inflammation-exacerbated cerebral inflammation under hypoxia in a CCL5-dependent manner.
Glucocorticoid signalling dysregulation and immune cell adaptation in Anorexia Nervosa.
Multifunctional Catechol-Functionalized Cellulose Hydrogels for the Minimally Invasive Treatment of Acute Optic Nerve Injuries.
Central microglia-adenosine-related signaling impairs bone-tendon interface repair via sympathetic ADRB2 activation.
Subcutaneous transplantation of lung organoids ameliorates vascular dementia via the IGFBP7-Ago2 mediated lung-brain axis.
DRP1 lysine 616 lactylation exacerbates cerebral ischemia-reperfusion injury by activating the STING inflammatory pathway.
Loss of microglial ATM drives synaptic pruning and cognitive impairment in epilepsy.
Mitochondrial microprotein MOCCI controls neuroinflammation by altering glial activation states.
Quantifying Heteromer Partitioning Reveals Inflammation-Dependent Redistribution of Microglial Adenosine A2A and Cannabinoid CB2 Receptors.
Mapping human microglial morphological diversity via handcrafted and deep learning-derived image features.
VISTA Deficiency Exacerbates Autoimmune Uveitis by Promoting Microglial Activation via the TLR4/MyD88/NF-κB Pathway.

Immunity. 2026 Jul 24. pii: S1074-7613(26)00275-X. [Epub ahead of print]

Disease-associated microglia adopt stage-specific phenotypes that regulate T cell fate and immunity in glioma.

Jiawen Qian, Chen Wang, Yi Zhang, Congwen Li, Yingying Zeng, Shuangyan Zhang, Fei Gao, Yiwen Zhu, Peiliang Cai, Zhongyuan Zhang, Yanan Hu, Xiaotong Yu, Benoit Kloeckner, Marco Moreira, Yuedi Wang, Bo Wang, Chujun Julia Zhao, Dan Zhang, Xi Chen, Shang Liu, Auriane Coutansais, Huangmijia Zhuang, Ronghua Liu, Feifei Luo, Liang Wu, Claudia Pasqualini, Yihua Chen, Xinyan Li, Mingfang Lu, Ziyi Li, Wei Guo, Svetoslav Chakarov, Zhaoyuan Liu, Bing Su, Rui Zhao, Yiwei Chu, Florent Ginhoux.

  Malignant gliomas are lethal brain tumors characterized by profound local immunosuppression and a radically remodeled myeloid landscape. Although these tumors mobilize resident microglia and infiltrating monocyte-derived macrophages, the mechanisms governing their phenotypic convergence and diversification remain elusive. Here, we integrated single-cell profiling and spatial transcriptomics of glioma-associated microglia in the GL261 model. We identified distinct microglial states that aligned with tumor architecture, most notably Cst7-expressing disease-associated microglia (DAMs) that aggregated at the tumor invasive margin and exhibited a conserved transcriptional signature shared across various central nervous system pathologies. Interferon-γ and toll-like receptor signaling sequentially tuned stage-specific DAM features, including transient MHC-II expression and sustained PD-L1 upregulation, thereby recalibrating the local immune equilibrium by reshaping bidirectional DAM-T cell interactions during glioma progression. Our findings highlight microglial state transitions as a stage-specific layer of immune regulation in glioma that shapes T cell fate and support targeting microglial plasticity to rebalance anti-tumor immunity.

Keywords:  DAMs; MHC class II; PD-L1; disease-associated microglia; glioma; macrophage; microglia; microglia-T cell interaction; myeloid cells

DOI:  https://doi.org/10.1016/j.immuni.2026.06.024
Circ Res. 2026 Jul 20.

Small Extracellular Vesicles From Cardiomyocytes Activate Microglia Aggravating HFpEF.

Lintong Men, Qian Wang, Bowen Ren, Yu Cao, Min Du, Shengqi Huo, Moran Wang, Bingyu Huang, Dewei Peng, Xiaoli He, Lujin Wu, Sheng Li, Cuntai Zhang, Jiaogao Lv, Li Lin, Junyi Guo.

   BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is increasingly acknowledged as a major public health concern due to its complex pathophysiology, which involves neuroinflammation and sympathetic activation. The crosstalk between the heart and hypothalamic microglia in HFpEF, particularly the role of small extracellular vesicles (sEVs), remains insufficiently explored.
METHODS AND RESULTS: We constructed an HFpEF model in mice by combining a long-term high-fat diet with the nitric oxide synthase inhibitor l-NAME (N[ω]-nitro-l-arginine methyl ester). These mice exhibited microglial activation and hypothalamic inflammation. Microglial depletion with PLX3397 suppressed sympathetic activity and improved cardiac dysfunction in HFpEF. sEVs derived from the myocardium of HFpEF mice induced a proinflammatory M1 phenotype in microglia, leading to hypothalamic inflammation and sympathetic activation. Intraperitoneal injection of the sEV biogenesis inhibitor GW4869 reversed these changes in HFpEF mice. Similar pathological changes were observed in BV2 microglia treated with sEVs isolated from palmitic acid-treated HL-1 cardiomyocytes. Bioinformatic and RT-qPCR analyses revealed a notable upregulation of miR-200c-3p in sEVs derived from both HFpEF myocardial tissue and palmitic acid-treated HL-1 cardiomyocytes, as well as in microglia. A cardiomyocyte-specific miR-200c-3p sponge inhibited microglial activation, hypothalamic inflammation, and sympathetic activation in HFpEF mice. Conversely, a miR-200c-3p mimic exacerbated proinflammatory responses in BV2 cells, while a miR-200c-3p inhibitor prevented the transition to a proinflammatory phenotype. The antiinflammatory protein DUSP1 (dual-specificity phosphatase 1) was validated as a potential downstream target of miR-200c-3p in microglia.
CONCLUSIONS: Our study reveals that HFpEF prompts cardiomyocytes to release sEVs enriched with miR-200c-3p, leading to hypothalamic inflammation and evoking sympathetic outflow, which in turn exacerbates cardiac dysfunction. Focusing on sEV-mediated communication between cardiomyocytes and microglia may offer a new therapeutic approach for HFpEF.

Keywords:  animals; communication; heart failure; phenotype; stroke volume

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327765
Nat Commun. 2026 Jul 21. pii: 6976. [Epub ahead of print]17(1):

Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies.

Svenja-Lotta Rumpf, Felix L Strübing, Karsten Nalbach, Claudia Marina Vargiu, Giacomo Berg, Stefan F Lichtenthaler, Piero Parchi, Pan Gao, Weilin Chen, Matthias Brendel, Johannes S Gnörich, Alexander Bernhardt, Léa Dias Rodrigues, Günter U Höglinger, Jochen Herms, Thomas Koeglsperger.

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer's disease (AD), and AD with Lewy body pathology (AD + LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.

DOI: https://doi.org/10.1038/s41467-026-74961-6
Adv Sci (Weinh). 2026 Jul 23. e76717

Human Dental Pulp Stem Cell Secretome Restores Ischemic Stroke-Impaired Motor and Cognitive Functions by Reprogramming Redox and Inflammatory Signaling.

Kyung-Joo Seong, Sehoon Park, Sun-Woong Bae, Daseul Kim, Jin Ho Lee, Won-Seok Choi, Zee-Yong Park, Ji-Yeon Jung, Won-Jae Kim.

  Ischemic stroke induces oxidative stress, neuroinflammation, neuronal death, and synaptic dysfunction, leading to persistent motor and cognitive deficits. The human dental pulp stem cell (hDPSC) secretome is a promising cell-free therapeutic candidate containing neurotrophic, antioxidant, and immunomodulatory factors. Here, we investigated its therapeutic effects in a photothrombotic mouse model of ischemic stroke and CoCl2-induced hypoxic BV2 microglial cells. Proteomic profiling identified antioxidant-associated proteins, including SOD2, GSR, and GSTP1, and microglial phenotype-related candidates, including GRN, CSF1, and LRP1. hDPSC secretome treatment reduced stroke-induced infarct volume and attenuated stroke-increased neuronal apoptosis, neuronal ROS accumulation, and NF-κB-associated inflammatory signaling in the cortex and hippocampus. It also shifted microglial marker expression toward an M2-associated profile and improved stroke-impaired hippocampal neurogenesis, vascular remodeling, and synaptic organization. Proteomic analyses further identified coordinated changes in pathways related to oxidative phosphorylation, inflammatory responses, calcium signaling, SNARE-associated vesicular transport, and ROBO-Rho-associated cytoskeletal remodeling. These molecular and cellular changes were associated with improved motor coordination, spatial learning and memory, contextual memory, and anxiety-like behavior. These findings support the hDPSC secretome as a cell-free therapeutic candidate for post-stroke functional recovery linked to redox, inflammatory, neurovascular, and synaptic remodeling.

Keywords:  dental pulp stem cell secretome; ischemic stroke; microglial polarization; neuroinflammation; redox signaling; synaptic remodeling

DOI:  https://doi.org/10.1002/advs.76717
Adv Sci (Weinh). 2026 Jul 20. e76690

Identifying a Csmd3+ Microglial Subpopulation that Drives Cold-to-Hot Transition and Immune-Cure in Glioblastoma.

Hai-Feng Jiang, Pan-Pan Gao, Yu-Wen Du, Li-Qin Wu, En-Zhi Yin, Qi An, Ze-Hua Ding, Jin-Wen Shi, Ya Shu, Ruoqiao Chen, Feng Liu, Mingfeng Li, Xiao Qian Chen.

  Glioblastoma (GBM) is immunologically cold and responds poorly to immune-based therapies owing to its highly heterogeneous and immunosuppressive tumor microenvironment (TME). However, strategies to achieve a cold-to-hot transition remain elusive, and suitable research models are still lacking. Here, TME profiling classifies our refractory G422TN-GBM model as the TMEMed (heterogeneous immune populations, "cold") subtype of human GBM, which can be shifted toward the TMEHigh (immune-high, "hot") subtype by inhibiting TGF-β signaling. In the multi-drug regimen, only αTGF-β combining temozolomide chemoradiotherapy and αPD-1 achieves immune-cure (ICu, passing tumor rechallenge, 12.5%). ICu screening reveals a newly identified Csmd3+ microglial subset with innate immune memory potential, which likely initiates durable anti-GBM immune memory and closely associates with effective GBM therapy and favorable prognosis. MGOE• Csmd3 , BV2 (Csmd3-overexpressed microglial BV2) elicit robust anti-GBM effects and achieve a notably 100% tumor rechallenge success in G422TN-GBM mice via promoting TMEMed-to-TMEHigh remodeling. Taken together, our findings identify an immunologically cold TMEMed GBM mouse model and provide a proof-of-concept for microglia-based TME reprogramming and cell therapy in GBM.

Keywords:  Csmd3+ microglia; TME subtype; anti‐GBM immune memory; glioblastoma; αPD‐1

DOI:  https://doi.org/10.1002/advs.76690
Brain. 2026 Jul 23. pii: awag247. [Epub ahead of print]

Photobiomodulation of immune crosstalk rescues neuroinflammation in Alzheimer's disease models.

Qi Shen, Haocai Chang, Junyu Li, Haoyun Guo, Wenbin Shi, Yihua Yan, Wenwen Ouyang, Zhan Zhang, Xiaolei Wu, Da Xing, Sihua Yang.

  Peripheral immune cell infiltration and crosstalk with brain-resident cells critically drive Alzheimer's disease (AD)-associated neuroinflammation, highlighting its therapeutic potential. Here, we found that photobiomodulation (PBM) markedly reduced cerebral CD8+ T cells infiltration in the cortex of AD (APP/PS1 and 3×Tg) mice, thereby improving cognition, and alleviating AD-related pathology by mitigating neuronal damage and gliosis. Immunofluorescence and transcriptomic analyses revealed that PBM inhibited the release of chemokines and pro-inflammatory cytokines from microglia, reducing endothelial adhesion molecules-mediated T cell migration. Concurrently, reduced secretion of tumor necrosis factor-α, interleukin-1α, and complement component 1q by pro-inflammatory microglia further diminished neurotoxic A1 astrocyte induction. Genetic overexpression or pharmacological inhibition further validated that PBM disrupted microglia NOD-like receptor protein 3 inflammasomes activation, attenuating astrocyte reactivity and T cells recruitment. These findings collectively suggest that the PBM-induced modulation of crosstalk between microglia, astrocytes, and CD8+ T cells is closely related to cognitive improvement. Reprogramming central-peripheral immune crosstalk with PBM resolves neuroinflammation and restores cognition in AD models-a translatable strategy for combating neurodegeneration.

Keywords:  Alzheimer’s disease; CD8+ T cells; central-peripheral immune crosstalk; neuroinflammation; photobiomodulation

DOI:  https://doi.org/10.1093/brain/awag247
Neuro Oncol. 2026 Jul 21. pii: noag151. [Epub ahead of print]

Programmable microfluidic modeling of the glioblastoma immune microenvironment recapitulates temporally regulated tumor-immune signaling.

Seokgyu Han, Yona Kim, Sein Kim, Chanyang Lee, Jaehyun Lee, Min-Hyeok Kim, Hyo Eun Moon, Sarnai Amartumur, Chaejeong Heo, Sun Ha Paek, Sungsu Park.

   BACKGROUND: Glioblastoma (GBM) progression is driven by intricate interactions between neoplastic cells and immune populations within the tumor microenvironment (TME), yet the temporal organization of these processes remains insufficiently defined. While tumor-associated macrophages (TAMs), composed of microglia and monocyte-derived macrophages, constitute a major immune population in GBM, microglia play a prominent role in shaping local immunosuppressive niches, thereby limiting cytotoxic lymphocyte infiltration. However, static co-culture models constrain interrogation of dynamic tumor-immune signaling.
METHODS: We utilized a programmable multi-inlet microfluidic platform that allows sequential, order-specific introduction of immune cells into GBM constructs, enabling controlled interrogation of MG- and natural killer (NK)-mediated interactions under defined temporal conditions. Bulk transcriptomic profiling and single-cell analyses were used to characterize tumor- and immune-associated pathways elicited by distinct temporal configurations.
RESULTS: In triculture constructs containing identical populations of GBM cells, microglia, and NK cells, MG-first delivery preferentially activated STAT3-associated immunoregulatory transcriptional programs, whereas NK-first delivery induced cytotoxic and interferon-related gene expression profiles. IL12A expression was selectively increased under NK-first conditions and correlated with immune-active GBM states in patient datasets. STAT3 inhibition reduced MG-associated suppression, increased IL12A expression, and enhanced the response to temozolomide.
CONCLUSIONS: This programmable spheroid platform not only recapitulates hallmark features of the GBM immune microenvironment but also uncovers temporally regulated pathways arising from sequential cellular interactions. By enabling controlled reconstruction of dynamic tumor-immune signaling, this system offers a versatile strategy for mechanistic investigation and provides a foundation for evaluating immune-modulatory approaches and microenvironment-targeted interventions in GBM and other malignancies.

Keywords:  Glioblastoma; IL-12p35; immune dynamics; microglia; natural killer cells

DOI:  https://doi.org/10.1093/neuonc/noag151
Acta Neuropathol. 2026 Jul 20. pii: 7. [Epub ahead of print]152(1):

Complement dysregulation during the early phases of synucleinopathy.

Hina Khan, Mary Gifford, Arash Kordbacheh, Asher Bury, Spencer Panoushek, Allyson Cole-Strauss, Christopher J Kemp, Kelvin C Luk, Kathy Steece-Collier, Nathan C Kuhn, Nicholas M Kanaan, Caryl E Sortwell, Joseph R Patterson, Matthew J Benskey.

  Parkinson's disease (PD) is characterized by progressive degeneration of nigrostriatal dopamine neurons and synucleinopathy, which is the accumulation of aggregated α-synuclein (α-syn). Increasing evidence implicates α-syn-associated neuroinflammation as a contributor to PD pathogenesis, yet immune mechanisms linking synucleinopathy to neurodegeneration remain incompletely defined. Activation of the complement cascade occurs in PD and other synucleinopathies, but most studies report complement activation after overt neurodegeneration, making it difficult to conclude if complement is directly activated by pathological α-syn or secondarily following neurodegeneration. We used the rat α-syn preformed fibril (PFF) model, in vitro complement assays and postmortem human PD tissue to investigate whether pathological α-syn directly activates complement prior to overt neurodegeneration. The α-syn PFF model exhibits a protracted pathological time course and distinct temporal separation between peak α-syn aggregation and nigrostriatal degeneration. Thus, we quantified complement expression, activation, and regulation during the aggregation phase. Synucleinopathy caused complement activation prior to nigrostriatal degeneration, including upregulation of components of both the classical (C1qa, C1r, C4b) and alternative (Cfd, Cfb) pathways, the anaphylatoxin (C3aR, C5aR) and phagocytic (CR3) complement receptors, and activation of complement C3. During early synucleinopathy microglia upregulated C3, which significantly correlated with synucleinopathy burden across several brain regions, including the substantia nigra pars compacta (SNc) and cortex. Concurrently, complement regulators, including Cd55, Cd59, neuronal pentraxin-1 (Nptx1), and the neuronal pentraxin receptor were downregulated in the synucleinopathy-affected SNc. Importantly, increased levels of C1q and iC3b along with downregulation of CD55 and NPTX1 protein were also observed in human postmortem PD SNc tissue, supporting the translational relevance of our findings. Mechanistically, we demonstrate that aggregated, but not monomeric, α-syn directly binds C1q and activates the complement cascade in a C1q-dependent manner. These data provide the first in vivo evidence that synucleinopathy triggers complement activation and dysregulation prior to neurodegeneration.

Keywords:  Alpha-synuclein; Complement system; Neurodegeneration; Neuroinflammation; Parkinson’s disease; Synucleinopathy

DOI:  https://doi.org/10.1007/s00401-026-03057-8
Cell Death Differ. 2026 Jul 24.

PLIN2-PGAM5-regulated lipid droplet-mitochondria contacts drive microglial neuroinflammation after spinal cord injury via fatty acid metabolic reprogramming.

Daoqiang Huang, Hong Li, Yiqian Luo, Pan Jiang, Haojie Zhang, Dingzhong Cheng, Longyou Xiao, Kuileung Tong, Jiale He, Zengbo Lu, Xuantao Hu, Mao Pang, Senyu Yao, Limin Rong, Bin Liu.

Persistent neuroinflammation is a hallmark of central nervous system (CNS) injury, driving neuronal loss and functional deficits. While microglial lipid metabolic reprogramming, particularly lipid droplet accumulation, has been implicated in chronic inflammation, the underlying mechanisms remain poorly understood. Using single-cell transcriptomics, we identified a previously defined lipid droplet-accumulating microglia (LDAM) subpopulation in spinal cord injury (SCI), characterized by elevated PLIN2 expression. Genetic deletion of Plin2 markedly reduced lipid droplet burden, attenuated neuroinflammation, and promoted neuronal survival and functional recovery in vivo. Mechanistically, PLIN2 interacts with the mitochondrial outer membrane protein PGAM5 to regulate lipid droplet-mitochondria contacts. This interaction inverts canonical metabolic flux by redirecting fatty acids from mitochondria back to lipid droplets, thereby suppressing β-oxidation and inducing mitochondrial dysfunction, which subsequently triggers STING-dependent inflammation. Notably, the PLIN2 220-392 domain is essential for PGAM5 binding and contact formation; disrupting this interaction attenuates STING signaling and enhances neuroprotection and functional recovery in vivo. Our findings identify the PLIN2-PGAM5 as a critical metabolic-immune pathway and suggest that targeting organelle-contact-mediated metabolic reprogramming represents a potential therapeutic strategy for CNS injury.

DOI: https://doi.org/10.1038/s41418-026-01815-5
J Adv Res. 2026 Jul 24. pii: S2090-1232(26)00597-7. [Epub ahead of print]

Microglia functions in peripheral inflammation-exacerbated cerebral inflammation under hypoxia in a CCL5-dependent manner.

Liang Guo, Xiangpei Yue, Xiaochang Zhang, Zhonghua Dai, Xiufang Jiang, Xuechao Fei, Wen Yang, Zibi Shi, Yaqun Jiang, Lu Chen, Xiang Cheng, Tong Zhao, Jingqi Shi, Jian Li, Hongjun Lin, Qi He, Jiangbo Li, Yang Yue, Qingyu Li, Shaojie Zhang, Jianjun Guo, Jiayue Gao, Ming Zhao, Haitao Wu, Lingling Zhu.

   INTRODUCTION: The role of peripheral inflammation (PI) in exacerbating hypoxic neuroinflammation is being recognized, with the underlying molecular mechanism largely unknown.
OBJECTIVES: This study is the first to map the single-cell atlas of cerebral immune microenvironment in mice under homeostasis, acute hypoxia (Hyp), LPS-induced PI, and PI-exacerbated hypoxic brain inflammation (Hyp/LPS).
METHODS: Six- to eight-week-old male C57BL/6J mice were subjected to hypoxic conditions in a decompression chamber (simulating 6000 m altitude) and/or intraperitoneal injection of LPS. Then 10X Genomics chromium single-cell transcriptomic analysis was employed to map the cerebral immune microenvironment of different mouse models, followed by flow cytometry analysis to validate the immune cells and microglial subpopulations identified in the brain and peripheral blood. Ccl5-knockout mice and primary microglia were also used to confirm the critical role of CCL5 in Hyp/LPS.
RESULTS: Nine transcriptionally distinct microglial subtypes are defined and classified into three functional groups based on the expression pattern of disease-associated microglia (DAM) and homeostatic genes. Ccl4+ microglia of DAM group, residing within hippocampus and cortex, represents the most responsive subtype to different stimuli. CCL5, with an increased serum level, is the top elevated cytokine in microglia upon Hyp/LPS. Hyp/LPS-induced cerebral inflammation is markedly reduced in Ccl5-knockout mice, and CCL5 neutralization restrains Hyp/LPS-increased expression of pro-inflammatory cytokines in primary microglia, indicating that Hyp/LPS-exacerbated neuroinflammation is mediated by CCL5.
CONCLUSION: Our study uncovers the key microglial subtype and cytokine in the peripheral and cerebral inflammation interaction in response to different stimuli, providing potential biomarker and therapeutic target for severe hypoxic neuroinflammation.

Keywords:  CCL4(+) microglia; CCL5; Cerebral inflammation; Hypoxia; Peripheral inflammation

DOI:  https://doi.org/10.1016/j.jare.2026.07.052
Mol Psychiatry. 2026 Jul 20.

Glucocorticoid signalling dysregulation and immune cell adaptation in Anorexia Nervosa.

Francesca Mottarlini, Lorenzo Da Dalt, Susanna Parolaro, Andrea Baragetti, Beatrice Rizzi, Sofia Taddini, Anna Chiara Cigognini, Francesca Vairano, Sara Bertelli, Armando D'Agostino, Fabrizia Bonacina, Giuseppe Danilo Norata, Fabio Fumagalli, Lucia Caffino.

Anorexia Nervosa (AN) is a neuropsychiatric disorder marked by compulsive weight-loss and hyperactivity, with poorly understood underlying mechanisms and limited treatment outcomes. Here we show that women with AN, at the first medical evaluation, exhibit hyperactivity and hypercortisolemia, together with a reduced immune cell count yet paradoxically showing increased levels of cell activation. One year later, only subjects considered in remission showed greater increases in cortisol and cytokine levels, along with enhanced monocyte differentiation and recruitment. Using the activity-based anorexia (ABA) rat model, we reproduced AN core features, including hypercorticosteronemia, and observed innate-skewed immune profiles, as well as persistent microglial and glucocorticoid receptor (GR) dysfunction in the ventral hippocampus. Pharmacological blockade of GR with RU486 attenuated hyperactivity and reshaped microglial phenotype in the ventral hippocampus. Our results suggest that cortisol elevation and immune cell adaptation may perpetuate disease vulnerability beyond weight normalization, challenging the notion of weight regain as an indicator of remission.

DOI: https://doi.org/10.1038/s41380-026-03756-4
Adv Healthc Mater. 2026 Jul 21. e71461

Multifunctional Catechol-Functionalized Cellulose Hydrogels for the Minimally Invasive Treatment of Acute Optic Nerve Injuries.

Kai-Hsiang Chang, Yi-Ke Lin, Wei-Li Chen, Ta-Ching Chen, Jiashing Yu.

  Oxidative stress-induced retinal ganglion cell degeneration is a major pathological feature of acute optic nerve injury, yet current posterior-segment therapies are limited by poor local retention and repeated invasive administration. Here, we developed an injectable catechol-functionalized carboxymethyl cellulose hydrogel, CMCDA, as a bioadhesive and antioxidative intravitreal platform. Through dopamine grafting and oxidative crosslinking, CMCDA exhibited shear-thinning injectability, self-healing behavior, wet-tissue adhesion, controlled biodegradability, and good biocompatibility. In an optic nerve crush model, CMCDA significantly reduced retinal reactive oxygen species (ROS) accumulation, preserved retinal ganglion cells, promoted axonal regeneration, and attenuated microglial activation, with 7 wt% CMCDA showing the strongest therapeutic efficacy. Single-cell RNA sequencing further suggested that CMCDA reshaped the injured retinal microenvironment by suppressing apoptotic, oxidative-stress, and inflammatory pathways while supporting phototransduction-related programs. Importantly, these structural and molecular benefits were accompanied by improved visual function, as confirmed by visual cliff testing and electroretinography. Overall, CMCDA represents a multifunctional cellulose-based hydrogel platform for minimally invasive antioxidative neuroprotection, axonal repair, and functional recovery after optic nerve injury.

Keywords:  antioxidant; bioadhesive; injectable hydrogel; neuroprotection; oxidative stress; retinal tissue repair

DOI:  https://doi.org/10.1002/adhm.71461
J Neuroinflammation. 2026 Jul 21.

Central microglia-adenosine-related signaling impairs bone-tendon interface repair via sympathetic ADRB2 activation.

Tingmo Huang, Liyang Wan, Ruixue Du, Liyue Zeng, Wenjie Li, Feifei Yuan, Hongbin Lu.

  Bone-tendon interface (BTI) injuries pose a major clinical challenge because surgical repair often fails to restore the native enthesis and its structural and mechanical integrity. Although local repair mechanisms have been extensively studied, whether central neuroimmune circuits contribute to BTI healing remains unclear. Here, using a murine rotator cuff injury model, we provide evidence that BTI injury engages a sensory-central-sympathetic regulatory axis that contributes to impaired repair. BTI injury activated sensory afferent signaling and was associated with microglia-mediated neuroinflammation in the hypothalamic paraventricular nucleus (PVN), reduced PVN neuronal activity, and increased central adenosine-related signaling. Chemogenetic activation of PVN microglia suppressed PVN neuronal activity, enhanced sympathetic-associated changes, and impaired BTI healing, whereas microglial inhibition produced the opposite effects. Metabolomic, microdialysis, and pharmacological analyses identified extracellular adenosine as a microglia-associated signaling mediator, likely involving A1R-expressing PVN neurons. Downstream, increased sympathetic signaling at the healing interface was associated with elevated β2-adrenergic receptor (ADRB2) activity and reduced osteogenic and chondrogenic factor expression. Local ADRB2 blockade improved molecular, structural, and histological indices of BTI repair, supporting ADRB2 as a peripheral effector node of this neuroimmune-sympathetic pathway. Together, these findings suggest that central microglia-adenosine-related signaling contributes to BTI repair impairment through sympathetic ADRB2 activation. Targeting central neuroimmune signaling or local ADRB2 activity may provide potential strategies for improving BTI healing.

Keywords:  Adenosine signaling; Bone-tendon interface; Microglia; Neuro-immune-skeletal axis; Paraventricular nucleus

DOI:  https://doi.org/10.1186/s12974-026-03977-y
J Neuroinflammation. 2026 Jul 20.

Subcutaneous transplantation of lung organoids ameliorates vascular dementia via the IGFBP7-Ago2 mediated lung-brain axis.

Qihang Luo, Jiajia Yang, Jiabao Huang, Nanhe Lin, Wenqing Liu, Ziyan Huang, Hongjiang Wang, Jiahui Yao, Jiayi Xiao, Haiyue Zhu, Xianshen Sha, Guangyao Liang, Yun Xie, Zhenwen Liang, Qiuhua Yu, Chuhuai Wang, Shengwei Jiang.

  Vascular dementia (VaD), whose leading cause is chronic cerebral hypoperfusion (CCH), currently has no approved effective disease-modifying therapies. The lung-brain axis mediates crosstalk between the lung and the nervous system, yet the specific mediators underlying its role in VaD remain unclear. This study demonstrated that subcutaneous transplantation of lung organoids (LO) ameliorated cognitive dysfunction in a mouse model of bilateral common carotid artery stenosis (BCAS). We showed that BCAS-induced CCH downregulated pulmonary expression of insulin-like growth factor-binding protein 7 (IGFBP7), a key mediator of the lung-brain axis. LO transplantation restoredcirculating IGFBP7, which translocated to the brain and acted directly on microglia by binding to Argonaute2 (Ago2), thereby inhibiting pro-inflammatory signaling pathways, reducing neurovascular damage and neuroinflammation, and alleviatingperipheral lung injury caused by CCH. Notably, LO transplantation concurrently restores cerebral function and pulmonary homeostasis, with concurrent recovery of endogenous pulmonary IGFBP7 expression in BCAS mice, indicating concurrent improvement of both brain and lung pathology through lung-brain axis crosstalk. This study confirmed that LO transplantation represented an effective biotherapy for VaD and identified the IGFBP7-Ago2 axis as a core regulatory pathway of the lung-brain axis. These findings provide mechanistic insights into the pathogenesis of VaD and highlight that IGFBP7 is a potential therapeutic target for restoring inter-organ crosstalk in dementia.

Keywords:  Chronic cerebral hypoperfusion (CCH); IGFBP7; Lung-brain axis; Organoids; Vascular dementia (VaD)

DOI:  https://doi.org/10.1186/s12974-026-03957-2
Cell Commun Signal. 2026 Jul 22.

DRP1 lysine 616 lactylation exacerbates cerebral ischemia-reperfusion injury by activating the STING inflammatory pathway.

Xiaoqi Ma, Dan Xin, Xianjia Li, Zhenhao Ying, Zifeng Li, Wenli Wang, Zhigang Mei, Jinwen Ge.

  Ischemia-hypoxia-induced inflammation and glycolysis are linked to the severity of cerebral ischemia-reperfusion injury (CIRI), but the mechanisms are unclear. Current research suggests that the inflammatory response of immune cells activated by STING is a key regulatory molecule in cellular inflammatory damage. However, the specific mechanisms underlying STING-mediated CIRI inflammatory responses remain unclear. This study found that STING expression was specifically elevated in microglia in the damaged side of the hippocampus in CIRI model mice, and this elevation was positively correlated with the severity of CIRI. Our previous research indicated that the dynamic process of mitochondrial fusion and fission is closely associated with CIRI. Building on this, we integrated glycolysis, mitochondrial fission, and the STING inflammatory pathway. Mechanistically, our data suggest that DRP1 K616 is a critical candidate site involved in DRP1 lactylation-associated regulation, which promotes STING pathway activation and contributes to the progression of CIRI. In conclusion, our findings offer substantial evidence that lactate-driven DRP1-mediated mitochondrial fission facilitates the involvement of the STING inflammatory pathway in CIRI. These results suggest that modulating lactate metabolism may serve as a crucial upstream strategy for therapeutic intervention in CIRI.

Keywords:  DRP1; Ischemic stroke; Lactylation; Microglia; Mitochondrial fission; cGAS-STING pathway

DOI:  https://doi.org/10.1186/s12964-026-03093-7
Free Radic Biol Med. 2026 Jul 18. pii: S0891-5849(26)00948-2. [Epub ahead of print]255 221-235

Loss of microglial ATM drives synaptic pruning and cognitive impairment in epilepsy.

Yang Hu, Jinyu Zhao, Youli Wang, Mingjuan Tan, Lei Wang, Honggang Qi, Jiurong Yang, Xinjian Zhu.

  Microglia are the resident immune cells of the central nervous system, highly sensitive to oxidative stress and essential for maintaining synaptic homeostasis. While epilepsy induces profound redox imbalance, how oxidative stress reshapes microglial function and disrupts synaptic integrity remains unclear. Here we show that epileptic seizures drive early loss of ataxia-telangiectasia mutated (ATM) protein in microglia, independent of canonical DNA damage responses. ATM deficiency shifts microglia into a hyperphagocytic state, with morphological activation and aberrant synaptic engulfment. Single-nucleus transcriptomic analysis of human temporal lobe epilepsy samples reveals that microglial subpopulations with reduced ATM expression display transcriptional signatures of activation, enhanced lysosomal processing, and synapse remodeling, accompanied by extensive rewiring of ligand-receptor interactions with neurons. Restoring ATM in microglia attenuates aberrant phagocytic activity and rescues synaptic integrity and cognitive function. Mechanistically, ATM sustains CREB phosphorylation to maintain G6PD-dependent NADPH production and antioxidant capacity, the disruption of which precipitates mitochondrial oxidative injury and excessive microglial synaptic pruning. Together, our findings reveal a DNA damage-independent ATM-CREB-G6PD axis that limits oxidative stress and maladaptive microglial phagocytosis, highlighting ATM loss as a key driver of synaptic pathology in epilepsy.

Keywords:  ATM; Cognitive impairment; Epilepsy; G6PD; Microglia

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.021
Front Immunol. 2026 ;17 1798798

Mitochondrial microprotein MOCCI controls neuroinflammation by altering glial activation states.

Kimberle Shen, Ke Guo, Sze Huey Leong, Radiance Lim, Wei Leong Chew, Cheryl Q E Lee, Lena Ho.

  Metabolic regulation and its underlying mechanisms play a critical role in controlling and resolving inflammation in the brain, directly shaping glial cell activation and the central nervous system's response to injury and disease. In our screen for microproteins that modify inflammatory outcomes, we discovered MOCCI (protein product of C15orf48/AA467197) as a significant regulator of gut and lung inflammation. However, its involvement in neuroinflammation is unknown. Here, we show that MOCCI is upregulated in microglia and astrocytes in both the mouse and human brain upon inflammation, and is required for orchestrating proper, complete, and beneficial activation of microglia and astrocytes. Induction of MOCCI triggers the transition of glia into a neuroprotective state and promotes the resolution of inflammation. In vitro, MOCCI deficiency leads to reduced migration, phagocytosis and cytokine secretion in microglia and astrocytes. In the cuprizone mouse model of multiple sclerosis, MOCCI plays a role in both demyelination and remyelination. These results position MOCCI as a molecular brake on neuroinflammation, highlighting its therapeutic potential for targeting glial metabolic health and resolving chronic CNS inflammation in neurodegenerative disease.

Keywords:  C15orf48; MOCCI; astrocytes; glia; glia activation; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1798798
Glia. 2026 09;74(9): e70200

Quantifying Heteromer Partitioning Reveals Inflammation-Dependent Redistribution of Microglial Adenosine A2A and Cannabinoid CB2 Receptors.

Rafael Franco, Jaume Lillo, Christian Griñán-Ferré, Mercè Pallàs, Rafael Rivas-Santisteban.

  G protein-coupled receptor (GPCR) heteromerization represents a key organizational mechanism in cell signaling, but it remains difficult to determine, in native cells, how receptor-associated signals are distributed between non-interacting and heteromer-associated states. Here, we address this limitation by combining proximity ligation assay (PLA) with the newly applied MolBoolean methodology, enabling in situ quantification of the partitioning of adenosine A2A and cannabinoid CB2 receptor-associated signals between non-interacting fractions and A2A-CB2 heteromeric complexes in primary microglia. We show that resting microglia contain detectable A2A-CB2 heteromers together with a substantial non-interacting A2A-associated signal fraction. Selective activation of either receptor promotes redistribution of the detectable receptor-associated signal toward the heteromer-associated fraction. Ligand-induced redistribution also occurred in HEK-293T cells expressing the two receptors. In contrast, pro-inflammatory activation of primary microglia with LPS/IFN-γ markedly changes the basal organization of the receptor system, increasing the proportion of MolBoolean-detectable signal associated with A2A-CB2 complexes, with approximately 70% of the detectable receptor-associated signal corresponding to heteromeric complexes. In this inflammatory context, further agonist-induced repartitioning is strongly limited compared with that observed in resting microglia. These findings identify inflammation-dependent receptor partitioning as a quantitatively measurable feature of microglial A2A and CB2 receptor organization and provide a framework for interpreting how receptor context may influence future studies of A2A-CB2 pharmacology under neuroinflammatory conditions.

Keywords:  GPCR heteromerization; MolBoolean; adenosine A2A receptor; cannabinoid CB2 receptor; in situ proximity ligation; microglial activation; neuroinflammation; precision pharmacology; receptor partitioning

DOI:  https://doi.org/10.1002/glia.70200
iScience. 2026 Jul 17. 29(7): 116575

Mapping human microglial morphological diversity via handcrafted and deep learning-derived image features.

Kayhan Alvandipour, Amélie Weiss, Mona Mathews, Brenda Besemer, Michaela Segschneider, Zahra Hanifehlou, Christian Felski, Michael Peitz, Arnaud Ogier, Peter Sommer, Oliver Brüstle, Johannes H Wilbertz.

  Microglia regulate brain health and disease through diverse, dynamic activation states, but capturing this continuous heterogeneity at scale remains challenging. We developed an imaging and analysis framework to map activation landscapes of human iPSC-derived microglia (iMG) at single-cell resolution. High-content imaging combined a hypothesis-driven immunofluorescence (IF) panel targeting NF-κB, ASC, and CD45 with a discovery-oriented cell painting (CP) assay. Phenotypes were quantified using handcrafted and representation-learning features. To classify cells, we applied Gaussian mixture models (GMMs), enabling soft probabilistic assignments that capture transitional states. Compared with graph-based methods such as Leiden, GMMs achieved similar performance while providing more interpretable descriptions of microglial heterogeneity. Deep-learning features from the targeted IF panel were most informative, yielding high classification accuracy and strong correlation with biological readouts, including NLRP3 inflammasome activation. This platform offers a scalable approach to quantify microglial states and provides a scalable platform for discovering compounds that modulate microglial phenotypes.

Keywords:  GMM; Gaussian mixture model; deep learning; high-content imaging; microglia heterogeneity; phenotypic profiling

DOI:  https://doi.org/10.1016/j.isci.2026.116575
Invest Ophthalmol Vis Sci. 2026 Jul 01. 67(8): 45

VISTA Deficiency Exacerbates Autoimmune Uveitis by Promoting Microglial Activation via the TLR4/MyD88/NF-κB Pathway.

Hui Feng, Baorui Chu, Xianyang Liu, Chao Wu, Fan Cao, Shuhao Zeng, Yakun Wang, Xinyuan Chen, Shangze Gao, Wenxian Yang, Hui Yang, Hong Wang, Shengping Hou.

Purpose: VISTA, an immune checkpoint enriched in microglia, regulates inflammatory signaling. Given microglial activation drives autoimmune uveitis, we investigated whether VISTA protects against experimental autoimmune uveitis (EAU) by modulating retinal microglia.
Methods: VISTA expression was analyzed by flow cytometry in active VKH patients and healthy controls. Functional studies in LPS/IFN-γ-stimulated BV2 microglia used genetic knockdown/overexpression and modulating antibodies (13F3, MH5A). Activation status, cytokine secretion, migration, and TLR4/MyD88/NF-κB signaling were assessed. An EAU mouse model received intravitreal adeno-associated virus-mediated VISTA overexpression, with severity evaluated clinically and histopathologically.
Results: VISTA was downregulated in circulating immune cells of VKH patients and in retinal microglia during EAU. In vitro, inflammatory stimuli reduced microglial VISTA. Its knockdown or blockade exacerbated microglial activation, pro-inflammatory mediator secretion (TNF-α, iNOS, COX2), and migration, while overexpression or agonism suppressed activation. Critically, intravitreal VISTA overexpression alleviated EAU severity. Mechanistically, VISTA deficiency potentiated activation by enhancing TLR4/MyD88/NF-κB signaling.
Conclusions: VISTA is a crucial gatekeeper of ocular immune homeostasis. Its downregulation promotes uveitis via microglial TLR4/MyD88/NF-κB pathway activation, making VISTA signaling restoration a promising therapeutic strategy.

DOI: https://doi.org/10.1167/iovs.67.8.45