bims-microg 2026-08-02 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–08–02
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy.
Transcriptional regulation of disease-relevant microglial activation programs.
Human-specific SRGAP2 paralogs synchronize neotenic microglial maturation and synaptic development.
Ultrasound-gated nanobubbles for sequential pyroptosis blockade and mechanotransductive neurorepair in sepsis-associated encephalopathy.
Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia.
Estradiol Reprograms Microglia to Create an Immune‑Suppressed Niche Permissive to Breast Cancer Brain Metastasis.
Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer's disease.
Diazonium-Enabled Post-Synthetic Construction of Enantiomeric Single-Atom Nanoagents Used for Alzheimer's Disease Treatment.
Oral exposure to non-brain-penetrable microplastics induces neurotoxicity via disrupting the gut microbiota-tryptophan metabolism-microglial autophagy cascade.
Microglial cGAS-STING-C1q axis mediates dopaminergic synaptic pruning and motor dysfunction in Mn-induced neurodegeneration.
Perfluorooctanoic acid exposure induces visual impairment via microglia-mediated neuroinflammation and retinal ganglion cell apoptosis.
Exercise alleviates neuroinflammation and cognitive decline in aged mice via hepatic FGF21-driven microglial mitophagy.
Microglia regulate sleep and thermoregulatory stability.
Targeted HA@Que-Mn nanozymes alleviate postherpetic neuralgia by modulating neuroinflammation.
Ginseng-derived exosomes loaded in fibrin gel promote retinal ganglion cell survival in glaucoma by exerting anti-inflammatory effects through modulating microglial polarization.
Forsythoside A alleviates experimental autoimmune encephalomyelitis by targeting Tnfaip2.
CCR5 drives glucose metabolic reprogramming to control microglial synaptic pruning via histone lactylation in a mouse model of depression.
MITD1 restricts HIV-1 release by targeting ESCRT-III proteins.
Sex differences in somatosensory circuitry are programmed by developmental microglia-astrocyte interaction.
Anti-inflammatory CAR-microglia targeting Aβ for Alzheimer's disease therapy.

Nat Neurosci. 2026 Jul 29.

cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy.

Yige Huang, Li Fan, Man Ying Wong, Zhuofan Lei, Balaji Krishnamachary, Daphne Zhu, Mika P Cadiz, Ravi Kumar Nagiri, Pearly Ye, Kendra Norman, Maitreyee Bhagwat, Young Jae Lee, Hui Li, Jingjie Zhu, Sadaf Amin, Kelli Lauderdale, Hao Chen, Wenjie Luo, Shiaoching Gong, Benjamin L Liechty, Jorge J Palop, Subhash C Sinha, Junfang Wu, Mingrui Zhao, Li Gan.

Epilepsy is a prevalent neurological disease, with one-third of individuals becoming nonresponsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we identify activation of cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN) signaling, in human DRE brain tissue. Microglia from individuals with DRE exhibit a robust type I IFN signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we similarly detect activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS attenuates seizure phenotypes, reduces glial inflammatory signatures and normalizes neuronal transcriptomic changes in mice with Dravet syndrome. Together, these findings identify cGAS-mediated neuroimmune signaling as a contributor to seizure pathology in Dravet syndrome and highlight this pathway as a potential therapeutic target.

DOI: https://doi.org/10.1038/s41593-026-02384-z
Neuron. 2026 Jul 29. pii: S0896-6273(26)00530-1. [Epub ahead of print]

Transcriptional regulation of disease-relevant microglial activation programs.

Amanda McQuade, Reet Mishra, Venus Hagan, Weiwei Liang, Peter J Colias, Vincent Cele Castillo, Bianca Gonzalez, Justin P Lubin, Verena Haage, Victoria Marshe, Masashi Fujita, Thomas Ta, Layla Gomes, Olivia Teter, Xia Han, Nathaniel Robichaud, Sarah E Chasins, Jessica E Rexach, Philip L De Jager, James K Nuñez, Martin Kampmann.

  Microglia, the brain's innate immune cells, can adopt a wide variety of activation states relevant to health and disease. Dysregulation of microglial activation occurs in numerous brain disorders, and driving or inhibiting specific states could be therapeutic. To discover regulators of microglial activation states, we conducted CRISPR interference screens in induced pluripotent stem cell (iPSC)-derived microglia for inhibitors and activators of six microglial states. We characterized 31 regulators at the single-cell transcriptomic and cell-surface proteome level in two distinct iPSC-derived microglia models, uncovering protein markers of relevant states. We functionally characterized several multi-state regulators. ZNF532 and PRDM1 knockdown drive disease-associated, lipid-rich signatures and enhance phagocytosis while showing opposing effects on antigen-presentation signatures. DNMT1 knockdown results in widespread loss of DNA methylation, activating negative regulators of interferon signaling. These findings provide a framework to direct microglial activation to selectively enrich microglial activation states, define their functional outputs, and inform future therapies.

Keywords:  CRISPR; DNMT1; PRDM1; STAT2; ZNF532; disease-associated microglia; interferon; microglia; microglial activation; phagocytosis

DOI:  https://doi.org/10.1016/j.neuron.2026.07.001
Neuron. 2026 Jul 22. pii: S0896-6273(26)00536-2. [Epub ahead of print]

Human-specific SRGAP2 paralogs synchronize neotenic microglial maturation and synaptic development.

Carlos Diaz-Salazar, JaeYeon Kim, Marine Krzisch, Juyoun Yoo, Patricia R Nano, Aparna Bhaduri, Rudolf Jaenisch, Mercedes Paredes, Franck Polleux.

  The human brain is distinguished by unusually prolonged developmental timing, yet the genetic mechanisms coordinating this neoteny across cell types remain incompletely understood. Here, we show that human cortical microglia undergo neotenic structural and transcriptional maturation relative to mouse microglia. We identify SRGAP2B/C, human-specific paralogs of the ancestral SRGAP2A, as the only human-specific gene duplications expressed in human microglia. Using xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that human-specific SRGAP2B/C, previously shown to reduce SRGAP2A protein abundance, are both necessary and sufficient to induce neotenic structural microglial maturation. Our results reveal that neotenic microglial maturation modifies the timing of synaptic development, linking microglial developmental programs to the timing of circuit formation. Together with previous evidence for neuronal SRGAP2A function, our results suggest that the human-specific SRGAP2B/C paralogs coordinated the emergence of neotenic synaptic development by acting in both neurons and microglia during human brain evolution.

Keywords:  brain; evolution; human; human-specific gene duplication; microglia; mouse; neoteny; neurons; synapses; xenotransplantation

DOI:  https://doi.org/10.1016/j.neuron.2026.07.007
Biomaterials. 2026 Jul 20. pii: S0142-9612(26)00499-0. [Epub ahead of print]336 124475

Ultrasound-gated nanobubbles for sequential pyroptosis blockade and mechanotransductive neurorepair in sepsis-associated encephalopathy.

Xiao Wang, Yang Liu, Mingxi Li, Huiting Xu, Yongxu Ju, Lin Cui, Ling Liu, Fang Yang.

  Sepsis-associated encephalopathy (SAE) is a life-threatening neuroinflammatory complication of sepsis for which effective treatment remains unavailable. A major challenge is that most therapeutics cannot efficiently cross the blood-brain barrier or simultaneously address the coupled pathological processes driving disease progression, namely microglial pyroptosis and impaired neurotrophic support. Here, we report an ultrasound-gated nanobubble platform designed for SAE that enables sequential pyroptosis blockade and mechanotransduction-mediated neurorepair. The platform consists of sphingosine-1-phosphate-functionalized, disulfiram-loaded nanobubbles (S1P@DSF-NBs), which actively accumulate in inflamed cerebral vasculature via the S1P-S1PR1 axis and serve as a localized reservoir for ultrasound-programmed intervention. Under a dual-ultrasound regimen, low-intensity pulsed ultrasound first induces stable nanobubble oscillation, mechanically activating Piezo1-dependent CREB-BDNF signaling in microglia to restore neurotrophic support. Subsequent high-intensity pulsed ultrasound triggers nanobubble destabilization and localized disulfiram release, leading to gasdermin D inhibition, suppression of pyroptosis, and attenuation of inflammatory amplification. In a murine SAE model, ultrasound-programmed S1P@DSF-NBs reduced systemic and hippocampal inflammation, decreased neuronal loss by 40 %, and improved cognitive performance by 2.24-fold, while reprogramming microglia toward a neuroprotective phenotype and disrupting the pyroptotic inflammatory cascade. These findings demonstrate that ultrasound-programmed nanobubble therapy can concurrently interrupt inflammatory injury and restore neuroprotective signaling in SAE. This work establishes an actively targeted, ultrasound-responsive biomaterials strategy for ultrasound-programmed intervention in SAE and offers a versatile framework for the treatment of other neuroinflammatory disorders.

Keywords:  Mechanotransductive neurorepair; Pyroptosis blockade; S1P receptor targeting; Sepsis-associated encephalopathy; Ultrasound-gated nanobubbles

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124475
Sci Adv. 2026 Jul 31. 12(31): eadz6517

Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia.

Alessandro Venturino, MohammadAmin Alamalhoda, Thomas Negrello, Kelly Jin, Cindy T J van Velthoven, Ryan John A Cubero, Jake Yeung, Peter Koppensteiner, Bosiljka Tasic, Sandra Siegert.

Anesthesia recovery is critical for resuming normal physiological and neuronal functions; however, the mechanisms involved remain elusive. Here, we identify a female-selective corticosterone-mediated microglia-neuron interaction during ketamine anesthesia recovery, absent in males. This microglia-neuron interaction induces plastic and functional neuronal changes, as evidenced by increased mEPSC frequency, which was occluded upon microglia depletion. We showed that this process is driven through up-regulation of the stress-responsive co-chaperone Fkbp5 mRNA and its protein, Fkbp51, in female microglia. Fkbp5/Fkbp51 is a key intermediary in a corticosteroid-induced stress response, and its involvement points toward a critical interface between endocrine signaling and microglia. To counteract the observed ketamine anesthesia-mediated increase in blood corticosterone during recovery, we removed the primary source of corticosterone by adrenalectomy. Close microglia-neuron interaction was reduced and increased again following corticosterone injection. Our findings identify a sex-specific microglia-mediated mechanism of neuronal plasticity during anesthesia recovery, driven by corticosterone, thereby enhancing our understanding of sex differences in brain function.

DOI: https://doi.org/10.1126/sciadv.adz6517
Neuro Oncol. 2026 Jul 29. pii: noag173. [Epub ahead of print]

Estradiol Reprograms Microglia to Create an Immune‑Suppressed Niche Permissive to Breast Cancer Brain Metastasis.

Karen L F Alvarez-Eraso, María J Contreras-Zárate, Andrew Goodspeed, James Costello, Jenny A Jaramillo-Gómez, Stella Koliavas, R Alejandro Marquez-Ortiz, Morgan S Fox, Vesna Tesic, Qian Fang, D Ryan Ormond, Peter Kabos, Mercedes Rincon, Diana M Cittelly.

   BACKGROUND: Young age is an independent risk factor for the development of breast cancer brain metastases (BM). Prior work showed that 17β-estradiol (E2), the predominant premenopausal hormone, promotes BM of tumors intrinsically unresponsive to E2, in part through modulating estrogen receptor-alpha expressing (ERα⁺) glial cells. However, how E2 reshapes the brain tumor microenvironment (TME), particularly microglia‑mediated immunity, and its impact to BM progression remains unclear.
METHODS: scRNA sequencing and multiparametric flow cytometry were used to define the impact of E2 and E2-suppression on brain immune-cell populations across different stages of BM progression using spontaneous and experimental models of BM. Depletion of microglia and T-cell co-cultures were used to study microglia's role in E2-induced BM. The effects of E2-suppression alone or in combination with whole brain radiotherapy were tested in preclinical models mimicking late-stage BM.
RESULTS: E2 repressed immune surveillance and immune activation programs in microglia from early to late stages of brain metastatic progression, suppressing recruitment of effector immune cells to BM. Estrogen suppression, in turn reactivated anti-tumoral signaling in microglia and increased recruitment of effector immune cells to the brain. Microglia from E2-treated BM-bearing mice showed a reduced capacity to promote T-cell expansion, effector potential, and CD8⁺T cell-mediated tumor cell killing. Conversely, E2-suppression reactivated an effective anti-tumoral response and synergized with RT to significantly decrease BM progression.
CONCLUSION: These findings reveal a previously unrecognized mechanism by which E2 accelerates BC‑BM progression through microglial immunosuppression and support evaluation of endocrine therapies as adjunct treatments for ER⁻ breast cancer brain metastases.

Keywords:  Brain metastasis; estrogen; metastatic triple-negative breast cancer; microglia; tumor microenvironment

DOI:  https://doi.org/10.1093/neuonc/noag173
Acta Neuropathol. 2026 Jul 29. pii: 12. [Epub ahead of print]152(1):

Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer's disease.

Netherlands Brain Bank

  Visual dysfunction is increasingly recognized as an important feature of Alzheimer's disease, and substantial retinal changes have been documented across multiple studies. Yet the molecular changes underlying retinal neurodegeneration and which retinal protein signatures best track cerebral pathology remain incompletely defined. Here, we performed comprehensive mass spectrometry-based proteomics on paired retinal and hippocampal tissue from the same postmortem donors (8 AD, 8 non-demented controls) to identify disease-associated molecular signatures and assess their overlap between these tissues. Using a sequential dual-extraction protocol, we identified 372 differentially abundant retinal proteins in AD, including established APP-processing regulators (SORL1, BACE1) and synaptic proteins. Retinal proteomes clearly separated AD from controls in principal component analysis, indicating robust AD-related molecular differences in the retina. Notably, 87% of proteins were detected in both retina and hippocampus, with 64 differentially abundant proteins shared between tissues, some of which showed strong cross-tissue correlation. Several retinal proteins also correlated with neuropathological disease stage. Functional enrichment analysis revealed convergent alterations in synaptic organization, cytoskeletal dynamics, mitochondrial function, cell adhesion, and APP metabolism in both tissues. Cell-type mapping using single-cell retinal reference data indicated that most proteomic changes were broadly distributed across cell types, though some proteins showed enrichment in specific populations, such as SORL1 in microglia and EYS in photoreceptors. The molecular changes identified here offer a potential basis for the retinal alterations previously documented through in vivo imaging and histological studies. Their similarities with brain pathology further support the retina as a promising window for assessing cerebral disease.

Keywords:  Alzheimer’s disease; Proteomics; Retina

DOI:  https://doi.org/10.1007/s00401-026-03054-x
Small. 2026 Jul 28. e74610

Diazonium-Enabled Post-Synthetic Construction of Enantiomeric Single-Atom Nanoagents Used for Alzheimer's Disease Treatment.

Junlin Ya, Mengmeng Liu, Yanjun Ji, Zhibo Tong, Bin Luo, Jingsen Bai, Jinsong Ren, Xiaogang Qu.

  Alzheimer's disease (AD) is driven by a self-amplifying interplay between oxidative stress and neuroinflammation, in which mitochondrial DNA (mtDNA) leakage-induced activation of the cGAS-STING pathway plays a central role. Strategies that solely eliminate reactive oxygen species (ROS) are insufficient to suppress downstream inflammatory cascades. Here, we report a pair of chiral dual-functional single-atom nanoagents that can simultaneously scavenge ROS and sequester leaked mtDNA. A diazonium-enabled post-synthetic modification strategy is employed to graft benzoic acid linkers onto a single-atom catalyst, enabling covalent conjugation of nona-arginine peptides with opposite chirality (L-/D-R9). The resulting constructs are further encapsulated by KLVFFAED peptides and tannic acid to yield L-/D-TKRM, conferring blood-brain barrier permeability and mitochondrial targeting. Both L- and D-TKRM effectively scavenge ROS and preserve mitochondrial function in Aβ-stimulated microglia, while D-TKRM exhibits enantioselectively prolonged mtDNA capture, more efficient suppression of cGAS-STING signaling, enhanced M2 microglial polarization, and superior neuroprotection. In vivo studies have demonstrated that these two nanoagents rescue cognitive function in 3 × Tg-AD mice, with D-TKRM showing better efficacy accompanied by reduced amyloid pathology, microglial activation, and neuronal loss. This work highlights diazonium chemistry as a new, versatile single-atom functionalization strategy and underscores that chirality is important for developing effective therapeutic agents for AD treatment.

Keywords:  Alzheimer's disease; cGAS‐STING pathway; diazonium chemistry; neuroinflammation; single‐atom catalysis

DOI:  https://doi.org/10.1002/smll.74610
J Hazard Mater. 2026 Jul 29. pii: S0304-3894(26)02107-2. [Epub ahead of print]515 143127

Oral exposure to non-brain-penetrable microplastics induces neurotoxicity via disrupting the gut microbiota-tryptophan metabolism-microglial autophagy cascade.

Yulong Wu, Zhouyan Dong, Dong Wang, Jiayi Dong, Xinze Jiang, Guangcheng Fu, Mei Cheng.

  The neurotoxic potential of microplastics (MPs) is an emerging environmental health crisis. However, the majority of environmental MPs are unable to penetrate the blood-brain barrier (BBB), leaving their mechanism of neurotoxicity largely unknown. Here, we show that oral exposure to pristine polystyrene MPs (which do not translocate to the brain) induces hippocampal-dependent cognitive deficits, impaired neurogenesis, and synaptic loss in mice, without detectable brain particle accumulation. This neurotoxicity is mediated by gut-brain axis disruption, characterized by gut microbiota dysbiosis, altered tryptophan metabolism, and increased permeability of both the intestinal barrier and the BBB. Crucially, hippocampal microglia exhibited a sustained pro-inflammatory shift (M1↑/M2↓) accompanied by defective autophagy. Fecal microbiota transplantation from healthy donors rescued the cognitive impairments and microglial dysfunction, establishing a causal role for the gut microbiota. Integrated multi-omics and correlation analyses identified the commensal bacterium Alloprevotella and the tryptophan-kynurenine metabolite 3-hydroxyanthranilic acid (3-HAA) as key mediators. In vitro, treatment of microglia with fecal supernatant from MPs-exposed mice recapitulated the M1/M2 imbalance, suppressed autophagy, and impaired brain-derived neurotrophic factor (BDNF) maturation. Remarkably, supplementation with 3-HAA restored autophagy in microglia, which in turn rebalanced their phenotypic polarization and rescued BDNF maturation. Our findings delineate a complete pathway from oral non-BBB-penetrable MPs exposure to cognitive dysfunction, orchestrated through the disruption of gut microbiota-3-HAA-microglial autophagy axis. This work unveils a fundamental indirect mechanism for the neurotoxicity of non-brain-penetrant environmental pollutants and identifies novel microbiota- and metabolite-centric targets for intervention.

Keywords:  Autophagy; Microglia; Microplastics; Neurotoxicity; Tryptophan metabolism

DOI:  https://doi.org/10.1016/j.jhazmat.2026.143127
J Hazard Mater. 2026 Jul 28. pii: S0304-3894(26)02100-X. [Epub ahead of print]515 143120

Microglial cGAS-STING-C1q axis mediates dopaminergic synaptic pruning and motor dysfunction in Mn-induced neurodegeneration.

Yang Hu, Honggang Chen, Jianjie Zhao, Jing Wang, Jingyuan Chen, Wenjing Luo, Jianbin Zhang.

  Environmental manganese (Mn) overexposure is a recognized risk factor for Parkinsonian-like neurodegeneration. Although synaptic loss is a crucial pathological hallmark of Mn neurotoxicity, the underlying cellular and molecular mechanisms are not fully understood. We demonstrate that Mn exposure induces motor dysfunction through aberrant microglial-mediated synaptic pruning. Pharmacological depletion of microglia effectively restores synaptic density and ameliorates motor deficits, establishing microglia as the primary drivers of this synaptic pathology. Mechanistically, Mn2 + activates the cGAS-STING pathway in microglia, which orchestrates the secretion of complement factor C1q and initiates the C1q/C3-CR3 complement cascade. This neuroimmune signaling results in complement-dependent tagging of dopaminergic synapses, triggering their targeted engulfment by activated microglia and consequent synaptic loss. Notably, blocking the STING pathway or neutralizing C1q function significantly attenuated excessive synaptic phagocytosis and prevented dopaminergic synapse loss, rescuing motor dysfunction in Mn-exposed mice. Together, our findings identify the cGAS-STING-C1q axis as a critical molecular driver of pathological synaptic pruning, highlighting a potential therapeutic strategy for treating neurological dysfunction in Mn-induced Parkinsonism.

Keywords:  Complement; Dopaminergic synapse; Manganese; Microglia; STING; Synaptic pruning

DOI:  https://doi.org/10.1016/j.jhazmat.2026.143120
Environ Int. 2026 Aug;pii: S0160-4120(26)00390-9. [Epub ahead of print]214 110432

Perfluorooctanoic acid exposure induces visual impairment via microglia-mediated neuroinflammation and retinal ganglion cell apoptosis.

Di Zhang, Bohan Liu, Bo Jiang, Wulian Song, Sisi Chen, Xiaoyu Zhu, Huiping Yuan, Jie Lian, Xinna Liu.

  Perfluoroalkyl and polyfluoroalkyl substances are closely associated with visual impairment; however, the pathogenic mechanisms through which they cause optic nerve damage and their relationships with the onset of ocular diseases remain poorly defined. In this study, a mouse model of perfluorooctanoic acid (PFOA) exposure was established by oral administration of PFOA (1 mg/kg/day) for 60 consecutive days to investigate the effects of PFOA on retinal ganglion cells (RGCs), the primary constituents of the optic nerve, and retinal microglia, the immune sentinels of the optic nerve. Retinal ischemia‒reperfusion (IR) is a key common pathological process of multiple vision-threatening ocular diseases. Comparisons of changes in visual function, retinal structure and key cellular biological processes between PFOA-exposed mice and IR-injured mice revealed that PFOA contributed to visual impairment by inducing microglia-mediated neuroinflammation and RGC apoptosis. Experiments using an in vitro coculture system further demonstrated that PFOA directly impaired RGCs by affecting mitochondrial function and indirectly caused RGC damage by triggering microglial activation and subsequent inflammatory cascades. Moreover, we observed that PFOA exposure increased retinal susceptibility and exacerbated neuroinflammation and RGC injury under pathological conditions, thereby accelerating disease progression and vision loss. This study reveals the mechanisms underlying PFOA-induced optic nerve damage and its potential role in promoting retinal disease progression, suggesting that PFOA may represent an environmental risk factor for visual impairment.

Keywords:  Ischemia–reperfusion; Microglia; Optic nerve damage; Perfluorooctanoic acid; Retinal ganglion cells

DOI:  https://doi.org/10.1016/j.envint.2026.110432
Brain Behav Immun. 2026 Jul 30. pii: S0889-1591(26)00683-5. [Epub ahead of print] 106935

Exercise alleviates neuroinflammation and cognitive decline in aged mice via hepatic FGF21-driven microglial mitophagy.

Pengda Li, Tao Wu, Mengjie Chen, Nan Wang, Xiaopeng Jia, Zengqiang Chen, Rui Duan.

  Aging-associated neuroinflammation is a major contributor to cognitive decline, and exercise is an effective non-pharmacological intervention against it. However, the molecular mechanisms linking peripheral adaptations to exercise with central neuroprotection in the aged brain remain incompletely understood. In this study, using aged male C57BL/6J mice subjected to 16-week treadmill exercise, we show that aerobic exercise improves cognitive function and attenuates hippocampal neuroinflammation. Through bioinformatic analysis, we identified fibroblast growth factor 21 (FGF21) as an exercise-induced yet aging-suppressed hepatokine. Notably, hepatic FGF21 knockdown eliminated the capacity of exercise to enhance hippocampal mitophagy, along with its beneficial effects on cognition and neuroinflammation. Pharmacological blockade of mitophagy recapitulated the loss of FGF21 function, similarly abolishing the exercise-induced cognitive improvements and attenuation of neuroinflammation. These findings suggest that the neuroprotective effects of FGF21 may be mediated through the promotion of mitophagy. Mechanistically, FGF21 activated the AMPK-transcription factor EB (TFEB) axis in microglia to restore lysosomal function and mitophagy. Restoration of microglial mitophagy was accompanied by reduced cytosolic mtDNA accumulation and attenuated cGAS-STING-driven neuroinflammation in the aged hippocampus. Together, our findings reveal a liver-brain axis through which exercise-induced hepatic FGF21 reshapes microglial homeostasis in the aging brain, and identify FGF21 as a potential therapeutic target for age-related cognitive decline.

Keywords:  Aerobic exercise; FGF21; Liver-brain axis; Mitophagy; Neuroinflammation

DOI:  https://doi.org/10.1016/j.bbi.2026.106935
Brain Behav Immun. 2026 Jul 30. pii: S0889-1591(26)00685-9. [Epub ahead of print] 106937

Microglia regulate sleep and thermoregulatory stability.

Nikolaas Steele, Grant S Mannino, Tabitha R F Green, Lindsey L Beauregard, Madison Szewczak, Sean M Murphy, Mark R Opp, Rachel K Rowe.

  Sleep fragmentation disrupts physiological homeostasis, including thermoregulation, metabolism, and immune signaling; however, cellular mechanisms that stabilize core body temperature and sleep architecture during disrupted sleep remain poorly understood. Microglia are the resident immune cells of the central nervous system and play a central role in integrating neuroimmune signaling with hypothalamic regulation of thermoregulation and sleep-wake control. We tested the hypothesis that microglia are required to maintain both thermoregulatory and sleep stability during physiological sleep and when sleep is disrupted. Male and female C57BL/6J mice (n = 128) were implanted with telemetry devices for continuous core body temperature monitoring and maintained on either a control diet or diet containing the CSF1R-inhibitor PLX5622 (PLX) to pharmacologically deplete microglia. Body temperature and sleep-wake behavior were assessed across a two-week depletion period and during a subsequent 7-day sleep fragmentation paradigm. Hierarchical models were used to quantify the effects of microglial depletion (via diet), sex, and time-of-day (light/dark period). Microglial depletion produced sex- and diet-dependent alterations in both thermoregulation and sleep measures. PLX increased body temperature in females early during the depletion period, after which body temperature normalized and subsequently declined to pre-PLX baseline values. In contrast, PLX minimally influenced outcome metrics in males. During sleep fragmentation, microglial depletion induced time-of-day-specific hypothermia in males and females during the dark and light periods, respectively. Notably, microglial depletion dissociated components of sleep in a sex-dependent manner: Total sleep time increased in females, whereas males exhibited reduced sleep-wake transitions, suggesting increased sleep consolidation and therefore distinct regulation of sleep quantity versus stability. Across experimental conditions, body temperature was a strong nonlinear predictor of sleep, with higher temperatures (>35°C) associated with substantially reduced total sleep time (5-10 min reduction for every 1℃ increase), particularly during the dark (active) period. These findings collectively suggest that microglia contribute to thermoregulatory processes and sleep stability in a sex-dependent manner, supporting a role for microglia in coordinating physiological homeostasis. Together, our results support a neuroimmune framework in which microglia may help coordinate thermoregulation and sleep, as microglial depletion was associated with dysregulation of both processes.

Keywords:  Core body temperature; Microglia; Neuroimmune signaling; Physiological stress; Sex differences; Sleep disruption; Sleep fragmentation; Thermoregulation

DOI:  https://doi.org/10.1016/j.bbi.2026.106937
Mater Today Bio. 2026 Aug;39 103423

Targeted HA@Que-Mn nanozymes alleviate postherpetic neuralgia by modulating neuroinflammation.

Yike Liu, Miao Zhao, Lu Li, Yuzong Yang, Siyi Wang, Ziqiang Lin, Jiahao Chen, Yupei Lai, Simin Tang, Xiangsheng Zhang, Xianping Wu, Jun Zhou.

  Postherpetic neuralgia (PHN), whose neuroimmune pathological mechanism remains unclear, is still an urgent clinical problem to be solved. In this study, we identified a key neurometabolic axis driving the occurrence of PHN, and developed a precise intervention strategy based on it. Cohort analysis based on the UK Biobank revealed that systemic inflammatory status was significantly associated with the risk of PHN. To translate this clinical association into actionable mechanistic targets, we integrated Mendelian randomization analysis with spinal cord transcriptomics data from a mouse PHN model, and found that functional deficiency of adenosine deaminase (ADA) was the core driver of the pro-inflammatory network. Mechanistic studies showed that specific downregulation of ADA expression in microglia led to pathological accumulation of local adenosine (ADO). Overloaded ADO broke the physiological analgesic homeostasis mediated by high-affinity A1/A3 receptors, and instead abnormally activated the low-affinity ADORA2B receptor pathologically upregulated in neurons, thereby triggering a neuroinflammatory cascade network that switched pain transmission from 'physiological analgesia' to 'pathological pro-inflammation'. Targeting this pathogenic pathway, we rationally designed a biomimetic nanozyme (HA@Que-Mn NPs). Through structure-oriented virtual screening, quercetin was selected as the conformational stabilizer of ADA; through manganese (Mn) coordination and surface functionalization with sodium hyaluronate (HA), the nanozyme was endowed with enhanced blood-brain barrier penetration ability, microglia-specific targeting and optimized catalytic efficiency of reactive oxygen species scavenging. In the resiniferatoxin (RTX)-induced mouse PHN model, systemic administration of the nanozyme effectively reshaped the neuroimmune microenvironment, inhibited pathological ADORA2B signal transduction, and achieved significant and long-lasting relief of neuropathic pain. This study established the ADA-ADO-ADORA2B pathogenic axis in PHN, and proposed a first-in-class nanozyme therapy with clinical transformation prospects, providing a new option for multi-omics driven targeted nanomedicine in the treatment of neuropathic pain.

Keywords:  ADORA2B receptor; Adenosine deaminase (ADA); Metal-polyphenol nanozyme; Microglia-neuron crosstalk; Postherpetic neuralgia (PHN)

DOI:  https://doi.org/10.1016/j.mtbio.2026.103423
Regen Biomater. 2026 ;13 rbag146

Ginseng-derived exosomes loaded in fibrin gel promote retinal ganglion cell survival in glaucoma by exerting anti-inflammatory effects through modulating microglial polarization.

Dengming Zhou, Dehong Tan, Xuanqi Peng, Cailian Fang, Yongzhen Yu, Haroon Iqbal, Junfan Zhang, Lin Fu, Lewei Tang, Xiaoyu Zhou, Xinyue Zhang, Run Xiao, Wenxiang Zhu, Ludan Yue, Yuanbo Liang.

  Glaucoma is the leading cause of irreversible blindness globally. Chronic neuroinflammation drives progressive retinal ganglion cell (RGC) loss independent of intraocular pressure, yet safe, sustained and precise neuroprotective modulation of the retinal inflammatory microenvironment remains a significant challenge. We developed an injectable fibrin gel delivery system loaded with ginseng-derived exosomes (GE-fibrin gel, GE-gel) to modulate microglial polarization, reduce retinal inflammation and promote RGC survival. In vitro, GE showed strong antioxidant and anti-apoptotic effects by getting rid of reactive oxygen species caused by oxidative stress and lowering apoptosis in R28 cells. Both GE and GE-gel stopped lipopolysaccharide from causing pro-inflammatory M1 polarization of microglia and increased anti-inflammatory M2 phenotypic change. Intravitreal injection of GE-gel suppressed pro-inflammatory microglial activation, diminished neuroinflammation and improved the survival of RGCs in a chronic ocular hypertension rat model. These results show that GE-gel could promote microglial polarization, change the immune environment in the retina and protect RGCs functionally over the long term. This approach may hopefully provide promising solutions for rapid and effective glaucoma therapy.

Keywords:  RGCs; ginseng-derived exosomes; glaucoma; hydrogel; microglia

DOI:  https://doi.org/10.1093/rb/rbag146
Chin Med. 2026 Jul 29. pii: 204. [Epub ahead of print]21(1):

Forsythoside A alleviates experimental autoimmune encephalomyelitis by targeting Tnfaip2.

Ping Tang, Guibao Luo, Huihui Xue, Chunsheng Yang.

   BACKGROUND: Multiple sclerosis (MS) is a debilitating neuroinflammatory disease. Experimental autoimmune encephalomyelitis (EAE) is a commonly used rodent model for MS. Forsythoside A (FA), a natural compound derived from Forsythia suspensa, exhibits anti-inflammatory and neuroprotective properties; however, its efficacy in EAE and its underlying mechanism remain unclear.
PURPOSE: To explore the therapeutic effect of FA on EAE and its mechanism.
METHODS: EAE was induced in C57BL/6 mice treated with FA (20/60 mg/kg) from day 7. Clinical scores, histopathology (H&E, LFB, immunofluorescence), flow cytometry, and spinal cord RNA sequencing were analyzed. Network pharmacology, molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR) were employed to identify and validate the target of FA. In vitro studies using BV2 microglia with Tnfaip2 knockdown/overexpression confirmed the mechanism via qRT-PCR and Western blot.
RESULTS: FA treatment dose-dependently alleviated clinical severity. While the 20 mg/kg dose showed a trend toward improvement without statistical significance, the 60 mg/kg dose significantly reduced CNS inflammation and demyelination. FA decreased peripheral Th1 cells in EAE mice. It suppressed microglial activation and pro-inflammatory markers (IL-1β, TNF-α, iNOS) expression. Transcriptomics and network analysis pinpointed TNF-α-induced protein 2 (Tnfaip2) in the TNF pathway. FA directly bound Tnfaip2 (KD = 28 µM), validated by docking, MD simulations, and SPR. In vitro, FA inhibited LPS-induced pro-inflammatory polarization and the Tnfaip2/NF-κB pathway in BV2 cells. Tnfaip2 overexpression abolished the anti-inflammatory effects of FA.
CONCLUSION: FA ameliorates EAE by suppressing pro-inflammatory microglial polarization via directly targeting Tnfaip2 and inhibiting the NF-κB pathway. This identifies the Tnfaip2/NF-κB axis as a potential therapeutic target for MS.

Keywords:  Experimental autoimmune encephalomyelitis; Forsythoside A; Microglial polarization; NF-κB pathway; Tnfaip2

DOI:  https://doi.org/10.1186/s13020-026-01476-z
Cell Rep. 2026 Jul 29. pii: S2211-1247(26)00827-2. [Epub ahead of print]45(8): 117749

CCR5 drives glucose metabolic reprogramming to control microglial synaptic pruning via histone lactylation in a mouse model of depression.

Ying-Ying Jiao, Zhu Zhu, Rui-An Wang, Ben-Yu He, Hang Yao, Zhi-Yong Zhou, Yun-Fan Shi, Cong Wang, Lei Cao, Yang Liu, Gang Hu, Ren-Hong Du, Ming Lu.

  Depression is linked to microglial activation, but the precise triggers and downstream pathways remain elusive. Through single-cell RNA sequencing of human blood samples, we find upregulation of the CCL5-CCR5 axis in patients with major depressive disorder. Using a chronic social defeat stress mouse model, we show that CCR5 is specifically elevated in activated hippocampal microglia. Microglia-specific deletion of CCR5 alleviates depressive-like behaviors and prevents microglial activation. Mechanistically, CCR5 binding to VHL stabilizes HIF-1α, redirecting microglial metabolism toward aerobic glycolysis. This metabolic shift results in lactate accumulation, which drives histone H4 lysine 12 lactylation (H4K12la). Genome-wide profiling reveals that H4K12la enrichment at complement gene promoters facilitates their transcription, ultimately leading to excessive microglial engulfment of neuronal spines and synaptic loss. Importantly, either inhibiting glycolysis or exogenous lactate supplementation can respectively rescue or mimic the pathological synaptic pruning and depressive-like behaviors. Our findings indicate a CCR5-driven immune-metabolic-transcriptional axis in microglia that underlies synaptic deficits in depressive-like behaviors, offering potential targets for therapeutic intervention.

Keywords:  CCR5; CP: neuroscience; depression; histone lactylation; metabolic reprogramming; metabolism; microglia; synaptic pruning

DOI:  https://doi.org/10.1016/j.celrep.2026.117749
Cell Rep. 2026 Jul 29. pii: S2211-1247(26)00851-X. [Epub ahead of print]45(8): 117773

MITD1 restricts HIV-1 release by targeting ESCRT-III proteins.

Jim Zoladek, Marion Cannac, Claire Lacouture, Emma Perdriau, Julien Burlaud-Gaillard, Philippe Roingeard, Delphine Muriaux, Sébastien Nisole.

  HIV-1 release from infected cells requires coordinated action of the viral Gag protein and the host endosomal sorting complexes required for transport (ESCRT) machinery. How innate immunity regulates ESCRT function to limit viral egress remains unclear. Here, we show that MITD1, a cell type-specific interferon-stimulated gene, is a potent inhibitor of ESCRT-dependent HIV-1 budding. MITD1 engages ESCRT-III subunits CHMP1B and CHMP4B, driving their incorporation into aggregates and impairing ESCRT-III assembly during HIV-1 budding. This disrupts the final steps of virion release, causing an accumulation of immature particles at the plasma membrane. MITD1 overexpression reduces HIV-1 release from cell lines, primary peripheral blood mononuclear cells (PBMCs), and human microglia, while sparing the release of ESCRT-independent viruses. These findings establish MITD1 as an interferon-stimulated restriction factor that limits HIV-1 egress by perturbing ESCRT-III assembly.

Keywords:  CP: microbiology; CP: molecular biology; ESCRT-III; HIV-1 egress; MITD1; innate antiviral immunity; interferon-stimulated genes; microglia; restriction factors; viral budding

DOI:  https://doi.org/10.1016/j.celrep.2026.117773
Cell Rep. 2026 Jul 25. pii: S2211-1247(26)00787-4. [Epub ahead of print]45(8): 117709

Sex differences in somatosensory circuitry are programmed by developmental microglia-astrocyte interaction.

Abigayle Duffy, Leigh Ellen Fremuth, Madison Doceti, JaQuinta Thomas, Charlotte Buswell, Osaretin Lawani, John R Lukens, Ukpong B Eyo.

  Men possess a greater density of cortical synapses in the adult brain relative to women, but the underlying mechanism and functional significance of this sex difference is unclear. Here, we identify a greater density of excitatory synapses in the male mouse somatosensory cortex (S1) which emerges during development and persists into the adult brain. We show that increased phagocytic activity in microglia of female mice causes a greater engulfment of astrocytes in the female S1 in a MERTK-dependent manner during a discrete developmental window, regulated at least in part by estrogen signaling. The resulting greater astrocyte density in males corresponds with an increase in astrocyte-derived synaptogenic factors, hevin and thrombospondin-2, which we propose leads to the observed sex difference in S1 synapse density. Moreover, we demonstrate that this sex difference in synapse density correlates with an increase in neuronal activity in the male S1 both in development and adulthood.

Keywords:  CP: neuroscience; astrocytes; glia; microglia; neurodevelopment; phagocytosis; sex differences

DOI:  https://doi.org/10.1016/j.celrep.2026.117709
Front Immunol. 2026 ;17 1820099

Anti-inflammatory CAR-microglia targeting Aβ for Alzheimer's disease therapy.

Xizhong Ding, Xukai Hu, Wanqiang Xue, Yingrui An, Wei Cheng, Shaolong Zhang, Anhua Lei, Jin Zhang.

  Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and chronic neuroinflammation, which together drive progressive neuronal loss and cognitive decline. In recent years, monoclonal antibodies targeting Aβ have demonstrated encouraging clinical benefits in Alzheimer's disease (AD). However, their therapeutic efficacy remains limited by insufficient and unsustained clearance of Aβ, as well as treatment-associated neuroinflammatory responses. These limitations highlight the need for alternative strategies that can achieve efficient Aβ elimination while maintaining immune homeostasis. To overcome these challenges, we developed a novel anti-inflammatory CAR-Microglia (CAR-Mic) incorporating a construct based on the TAM receptor family (TYRO3, AXL, and MERTK), which are key regulators of efferocytosis and anti-inflammatory responses. The resulting Aβ-targeted CAR-Mics showed enhanced Aβ engulfment and reduced proinflammatory cytokines release. Among the constructs tested, AXL-CAR demonstrated the most favorable overall performance and was therefore selected for the generation of human induced pluripotent stem cell (iPSC)-derived CAR microglia-like cells (CAR-iMGLs). In an AD mouse model, AXL-CAR-iMGLs exhibited enhanced Aβ clearance without evidence of severe adverse effects. Collectively, these findings establish TAM receptor-based CAR-iMGLs as a promising cell therapy model for AD and potentially other neurodegenerative disorders characterized by chronic neuroinflammation and defective pathological protein clearance.

Keywords:  Alzheimer’s disease; amyloid-β; chimeric antigen receptor; iPSC; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1820099