J Neuroinflammation [JOURNAL]
Sun
200 papers
Neonatal sevoflurane exposure disrupts the lung-brain axis and drives microglial neuroinflammation and cognitive deficits.
Liang L, Cao S, Zhao Y … +11 more , Liu B, Wang J, Gong P, Wang Y, Hao G, ZhangMu X, Lu N, Zhang H, Wu S, Kuang F, Zhang H
J Neuroinflammation · 2026 Apr · PMID 41981595 · Full text
BACKGROUND: Neonatal sevoflurane exposure in mice induces microglial activation and long-term cognitive deficits, a finding that raises significant concerns for pediatric anesthesia. The lung-brain axis, a critical pathw...
BACKGROUND: Neonatal sevoflurane exposure in mice induces microglial activation and long-term cognitive deficits, a finding that raises significant concerns for pediatric anesthesia. The lung-brain axis, a critical pathway mediating pulmonary-central nervous system communication, is indispensable for maintaining organismal homeostasis. However, existing research on anesthetic neurotoxicity has focused predominantly on central mechanisms, with insufficient attention to the lung-a major immune organ with extensive bidirectional crosstalk with the brain. Herein, we aim to explore the lung-brain interactions underlying long-term cognitive sequelae of neonatal sevoflurane exposure. METHODS: C57BL/6J mice were selected and exposed to 3% sevoflurane for 2 h daily on postnatal days 6-8. Upon reaching adulthood, cognitive function and microglial activation status were evaluated. At 4 weeks post-exposure, 16S rRNA gene sequencing and metabolomic analysis were performed respectively to characterize the structure of the pulmonary microbiota and the metabolite profile. Proximity ligation assay (PLA), fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer (FLIM-FRET), and co-immunoprecipitation (COIP) were employed to investigate the molecular mechanisms by which lung-derived metabolites mediate brain effects. Additionally, rescue experiments were conducted by administering the sphingosine-1-phosphate receptor modulator FTY720 and Moce to validate the aforementioned effects. RESULTS: Repeated neonatal sevoflurane exposure impaired adult cognitive function, induced microglial activation, and was concurrent with pulmonary microbiome dysbiosis and metabolic alterations. Notably, sphingosine-a key membrane lipid-was significantly decreased. Intratracheal administration of FTY720, a sphingosine analog, alleviated neuroinflammation and ameliorated cognitive deficits. Mechanistically, sevoflurane exposure upregulated HDAC1 and downregulated KLF4, whereas FTY720 significantly rescued these sevoflurane-induced expression aberrations, implicating the HDAC1/KLF4 axis in the regulation of neuroinflammation. Additionally, MOCE significantly alleviated neuroinflammation and ameliorated cognitive deficits. CONCLUSIONS: Developmental sevoflurane exposure induces microglial activation and cognitive decline via a pulmonary dysbiosis-sphingosine reduction cascade. The sphingosine-1-phosphate receptor modulator FTY720 mitigates this impairment by regulating microglial activation and neuroinflammation. These findings reveal novel mechanisms of anesthetic neurotoxicity and identify potential neuroprotective targets for pediatric anesthesia.
Insights and challenges on animal models for progressive multiple sclerosis.
Nalepa IF, Haahr NO, Bekiaris V … +3 more , Jakobsen MR, Asuni AA, Benmamar-Badel A
J Neuroinflammation · 2026 Apr · PMID 41981455 · Full text
Progressive multiple sclerosis (PMS) remains a major clinical challenge due to its complex pathophysiology and limited therapeutic options. While disease-modifying therapies have significantly improved prognosis for rela...
Progressive multiple sclerosis (PMS) remains a major clinical challenge due to its complex pathophysiology and limited therapeutic options. While disease-modifying therapies have significantly improved prognosis for relapsing forms of multiple sclerosis (RMS), effective treatments for the progressive, neurodegenerative phase are lacking. Animal models have been instrumental in elucidating the molecular mechanisms underlying multiple sclerosis (MS) pathology and have guided the drug development field for MS, yet their ability to faithfully replicate the development of PMS remains debated. The most frequently used animal models are either immune-mediated, viral, or toxin-induced demyelinating models, but none of these are able to fully mimic the complexity of PMS pathology. This review examines the immunopathological features of animal models of PMS and critically evaluates their strengths and limitations for studying the progressive stages of disease. We highlight the variability that currently exists in the experimental autoimmune encephalomyelitis (EAE) field, as methodologies vary between EAE model paradigms which limit comparability. We conclude that no single model recapitulates PMS, however, refined and combined approaches, with careful attention to strain, age, sex, and induction protocol, can improve translational relevance and support development of therapies targeting PMS.
Extensive peripheral immunoglobulin repertoire analyses in people with multiple sclerosis reveal disease-specific signatures and distinct treatment effects of disease modifying drugs.
Vasilenko N, Ruschil C, Stadelmaier J … +13 more , Tieck MP, Schembecker S, Owens GP, Bennett JL, Berthele A, Ziemann U, Poli S, Snaidero N, Nahnsen S, Jarboui MA, Bichmann L, Gabernet G, Kowarik MC
J Neuroinflammation · 2026 Apr · PMID 41981407 · Full text
BACKGROUND: B cells are crucial players in the pathogenesis of multiple sclerosis (MS), however, limited information is available on peripheral immunoglobulin (Ig) repertoires of people with MS (pwMS) in comparison to he...
BACKGROUND: B cells are crucial players in the pathogenesis of multiple sclerosis (MS), however, limited information is available on peripheral immunoglobulin (Ig) repertoires of people with MS (pwMS) in comparison to healthy individuals and during different treatments. METHODS: Next generation sequencing of Ig heavy chains (VH) originating from bulk-sorted B cell populations was performed in 33 pwMS and ten healthy controls. All 33 pwMS were examined longitudinally at baseline and six months after treatment with ozanimod, fingolimod, dimethyl fumarate, teriflunomide, cladribine or natalizumab. Ig peptides were obtained longitudinally in a subset of treated pwMS by Ig mass spectrometry, overlapped with VH transcriptomes through nf-core bioinformatics workflow analysis and additionally Ig serum level and anti-Epstein-Barr virus IgG level (EBNA1) were measured. RESULTS: VH repertoires of treatment-naïve pwMS showed a significantly decreased diversity in the double negative B cells and different usage of IGHV genes when compared with healthy controls. Quantitative changes in B cell subsets during treatment were accompanied by qualitative changes in Ig repertoires with a significantly decreased diversity in the naive, memory B cells and plasmablasts during ozanimod treatment. A similar trend was noticeable for all other treatments except natalizumab. No qualitative change in Ig peptides overlapping with Ig transcriptome repertoires was observed. CONCLUSIONS: This study provides first evidence for an altered peripheral Ig repertoire in pwMS. In addition, various treatments seem to shift the composition of B cells towards an increased fraction and activation of the naive B cell pool and a reduced fraction of memory B cells with reduced clonal diversity.
STING signaling in vestibular macrophages underlies Ménière's disease pathogenesis.
Liu J, Li N, Mu Y … +13 more , Song Y, Lu Y, Xu X, Zhang N, Wang J, Li X, Wang H, Wang Y, Fan Z, Lyu Y, Han Y, Zhang D, Wang H
J Neuroinflammation · 2026 Apr · PMID 41975489 · Full text
BACKGROUND: Ménière’s disease (MD) is a disabling inner-ear disorder. Although the key pathologic alteration of MD is characterized as endolymphatic hydrops (EH), the underlying pathogenic mechanism remains unclear, and...
BACKGROUND: Ménière’s disease (MD) is a disabling inner-ear disorder. Although the key pathologic alteration of MD is characterized as endolymphatic hydrops (EH), the underlying pathogenic mechanism remains unclear, and no definitive curative treatments are available. Emerging evidence implicates oxidative stress and innate immunity as key contributors to MD pathogenesis. METHODS: Human vestibular end organs were collected to characterize the reactive oxygen species (ROS) levels and the STING signaling activation, findings that were further corroborated in an LPS-induced EH mouse model. Transfection and transwell co-culture were performed to investigate the feedback loop between sensory epithelial cells and macrophages in vitro. Molecular biology experiments were performed to elucidate the underlying regulatory mechanisms. Additionally, STING and CUL4B deficiency mice were used to explore potential therapeutic targets in vivo. RESULTS: The oxidative stress, cytoplasmic dsDNA leakage, and STING activation were elevated in both MD patients and LPS-induced EH mouse model. The dsDNA released from ROS-damaged hair cells activates STING in vestibular macrophages. STING-specific knockout in macrophages alleviates EH, audio-vestibular dysfunction, and interferon-stimulated genes expression in mouse model. The CUL4B-DDB1-ROC1 complex ubiquitinates STING at K370, promoting its degradation and inhibiting activation. Notably, CUL4B deficiency exacerbates LPS-induced EH, audio-vestibular dysfunction, and interferon-stimulated genes (ISG) upregulation, while double conditional knockout reverses these effects. CONCLUSION: Our study demonstrates that STING activation in vestibular macrophages contributes to audio-vestibular dysfunction and modulating this pathway has promising beneficial effects on audio-vestibular function in EH mice model, which is a potential therapeutic strategy for MD.
Ependymal cell inflammatory activation in response to intracerebral hemorrhage.
Liu J, Lin H, He X … +18 more , Zheng Y, Wu J, He Q, Zhang C, Huang H, Yu X, Zhou Y, Chen Z, Zhou H, Fan L, Fu X, Tang T, Guan G, Yu X, Feng X, Du Y, Chen H, Chen J
J Neuroinflammation · 2026 Apr · PMID 41975484 · Full text
BACKGROUND: Neuroinflammation is a central pathological process in secondary brain injury following intracerebral hemorrhage (ICH). While inflammatory responses in perihematomal brain tissue have been extensively investi...
BACKGROUND: Neuroinflammation is a central pathological process in secondary brain injury following intracerebral hemorrhage (ICH). While inflammatory responses in perihematomal brain tissue have been extensively investigated, the contribution of ependymal cells to post-ICH neuroinflammatory responses and ventricular pathology remains poorly defined. METHODS: An autologous blood-induced ICH mouse model was used in combination with single-cell RNA sequencing and spatial transcriptomic analyses to characterize transcriptional reprogramming of ependymal cells. EGFP transgenic mice were used to trace the infiltration of peripheral immune cells. Clinical data was used to assess the association between C3 and hematoma volume. Complement pathway activation was evaluated through integrated single-cell transcriptomic analysis, spatial transcriptomic analysis, immunofluorescence staining, and western blot. Bst2-deficient mice were employed to investigate the mechanisms how complement pathway is regulated in ependymal cells. RESULTS: Single-cell and spatial transcriptomic analysis showed impaired ciliary function and reduced capacity for homeostatic maintenance in ependymal cells. Ventricular asymmetry showed positive association with cognitive impairment at 14-days post-ICH. In parallel, ependymal cells underwent transcriptional reprogramming toward immune and inflammatory phenotypes, accompanied by ipsilateral immune cell infiltration. Cell-cell communication analysis further indicated extensive bidirectional signaling between ependymal cells and multiple immune cell populations, particularly through the complement pathway. Consistent with these findings, elevated C3 expression was detected in ipsilateral ependymal cells. Clinically, circulating C3 levels were elevated in patients with basal ganglia hemorrhage and positively correlated with hematoma volume. Knock out of Bst2 downregulated C3 expression in ependymal cells. CONCLUSION: Following ICH, ependymal cells undergo a functional transition characterized by loss of cilia-dependent functions and gain of immune and inflammatory properties, including activation of the complement pathway, particularly C3, regulated by BST2.
Impaired removal of dying brain cells by microglia in Gpr34 deficient mice.
Bohannon DG, Geller A, Simmons SK … +9 more , Cintron JA, Martenis WE, Stalnacker K, Masse A, Kwon MJ, Zhang YL, Levin JZ, Kunwar PS, Sheng M
J Neuroinflammation · 2026 Apr · PMID 41964003 · Full text
GPR34, a G protein-coupled receptor present selectively in microglia and other myeloid cells, is highly expressed in homeostatic microglia but is downregulated in disease associated microglia (DAM) such as those found in...
GPR34, a G protein-coupled receptor present selectively in microglia and other myeloid cells, is highly expressed in homeostatic microglia but is downregulated in disease associated microglia (DAM) such as those found in Alzheimer’s disease brain. However, little is known about GPR34’s role in microglia function or brain development. Here, we studied Gpr34 knockout (KO) mice at postnatal 18-day (P18) and 3 months (3 mo) age. In the brains of P18 Gpr34 KO mice, there were elevated numbers of neurons, oligodendrocytes and microglia, many of which were IHC-positive for the cell death markers cleaved-caspase 3, phospho-RIP3, or annexin V. P18 KO animals showed a reduced localization of microglia in areas of high cell death, while the increased evidence of cell death way largely resolved in 3 mo animals. While the uptake of bacterial particles was not impacted ex-vivo, KO microglia showed increased intracellular accumulation of endogenous cargo, myelin basic protein (MBP) and synaptosomal-associated protein 25 (SNAP25), suggesting altered handling of apoptotic debris without a global phagocytic defect. Notably, transcriptomic analysis revealed persistent impact of immune pathways even at 3 months, at the stage where KO mice also displayed sustained hypolocomotion. Collectively, these results indicate that murine Gpr34 contributes to early clearance of dying cells and may influence a long-lasting impact on microglia state and behavior.
Clostridium butyricum ameliorates Toxoplasma gondii-induced neuropsychiatric disorders by attenuating glial-mediated synaptic pruning via the gut-brain axis.
Li Y, Wu H, Yang J … +14 more , Weedor JG, Ding H, Cui W, Cui B, He Z, Zhang W, Xing Y, Zeng F, Huang X, Zheng K, Shen Y, Yu Y, Pan W, Yang X
J Neuroinflammation · 2026 Apr · PMID 41963962 · Full text
Gut microbiota dysbiosis contributes to Toxoplasma gondii (T. gondii)-induced neuropsychiatric disorders (TNDs); however, the underlying mechanisms remain largely elusive. Here, we identified the critical role of butyrat...
Gut microbiota dysbiosis contributes to Toxoplasma gondii (T. gondii)-induced neuropsychiatric disorders (TNDs); however, the underlying mechanisms remain largely elusive. Here, we identified the critical role of butyrate-producing bacteria in TNDs in mice. Decreased abundance of butyrate-producing bacteria was consistently observed in patients with Alzheimer’s disease and T. gondii-infected mice. Dietary supplementation with Clostridium butyricum (C. butyricum), a gut commensal butyrate-producing bacterium, reversed gut microbiota dysbiosis, ameliorated intestinal barrier disruption and inflammation, and reduced endotoxemia. Coincidentally, C. butyricum administration suppressed microglial and astrocytic activation, rescued synaptic ultrastructure damage and synaptic loss, thus alleviating cognitive impairment and anxiety/depression-like behaviors. Mechanistically, C. butyricum treatment mitigated the abnormal synaptic pruning mediated by glial cells and C1q to prevent the neuropathology induced by T. gondii infection. Importantly, fecal microbiota transplantation from C. butyricum-supplemented mice into antibiotic-treated recipients recapitulated the therapeutic effects on gut and brain pathology observed in infected mice. Together, our findings suggest that C. butyricum ameliorates TNDs by modulating glial cell-mediated abnormal synaptic pruning via the gut-brain axis, highlighting the therapeutic potential efficacy of butyrate-producing bacteria against TNDs.
MIND-NL diet adherence moderates the relation of low-grade systemic inflammation with neuroinflammatory metabolites and cognitive functioning: an exploratory cross-sectional study in older adults.
Remie LB, van Loenen MR, van Trijp MPH … +6 more , de Lange IGS, Vermeiren Y, Mes JJ, Puts NA, Oosterman JM, Aarts E
J Neuroinflammation · 2026 Apr · PMID 41957664 · Full text
BACKGROUND: Observational studies have linked high adherence to the “Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay” (MIND) diet to improved cognitive functions in older ad...
BACKGROUND: Observational studies have linked high adherence to the “Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay” (MIND) diet to improved cognitive functions in older adults. The underlying peripheral and central mechanisms of this association remain poorly understood, although multiple nutrients in the MIND diet are known for their anti-inflammatory effects. Therefore, we explored the cross-sectional relation between MIND diet adherence (Dutch version), systemic inflammation, neuroinflammation, and cognitive functioning in older adults. In addition, we examined the role of intestinal barrier permeability in MIND diet associations with (neuro)inflammation. METHODS: We included 88 older adults (60–75 year) at risk of cognitive decline. MIND-NL diet adherence was assessed using a food frequency questionnaire. Systemic inflammation (C-reactive protein levels, white blood cell-counts and neutrophil-to-lymphocyte ratio) and intestinal barrier permeability (lipopolysaccharide-binding protein, zonulin, and lipopolysaccharide) markers were measured in blood. Neuroinflammation-associated metabolites (myo-inositol, choline and creatine) were measured in the dorsolateral prefrontal cortex with proton magnetic resonance spectroscopy (1H-MRS). Cognitive functioning was assessed with a neuropsychological test battery. RESULTS: Linear models showed that both MIND diet adherence and systemic inflammation did not predict neuroinflammation or cognition independently. However, MIND diet adherence significantly moderated the relation between systemic inflammation and neuroinflammation (β=-0.22, p = 0.04) as well as between systemic inflammation and cognition (β = 0.22, p = 0.02). Specifically, in individuals with lower MIND diet adherence (identified as scores ≤ 7), systemic inflammation was positively related to neuroinflammation, and negatively to cognition. Similarly, MIND diet adherence significantly moderated the relation between intestinal barrier permeability and neuroinflammation (β=-0.28, p = 0.05). Finally, within participants with lower MIND diet adherence (median split at ≤ 8.75), systemic inflammation mediated the relation between the intestinal barrier permeability and neuroinflammation (path coefficient = 0.427 [0.072; 0.891], p = 0.04). CONCLUSION: Our findings show that MIND diet adherence modulates inflammation-brain relationships in aging, with detrimental associations between systemic inflammation and both neuroinflammation and cognitive functioning observed only in individuals with lower adherence. Moreover, MIND diet adherence similarly modulates the systemic inflammation-mediated relationship between intestinal barrier permeability and neuroinflammation. These findings should be confirmed in randomized controlled trials.
Network-based disease fingerprinting with neuroinflammation PET imaging.
Barzon L, Maccioni L, Carranza Mellana M … +21 more , Schubert JJ, Brusaferri L, Cousins O, Rosenzweig I, Mizuno Y, Marques TR, Harrison NA, Fryer T, Bullmore ET, Mondelli V, Pariante C, Sharp D, Scott G, Pereira JB, Howes O, Sossi V, Bodini B, Stankoff B, Loggia ML, Turkheimer FE, Veronese M
J Neuroinflammation · 2026 Apr · PMID 41957656 · Full text
Neuroinflammation is a hallmark of numerous neurodegenerative, psychiatric, and chronic pain disorders and can be assessed in vivo with 18 kDa translocator protein (TSPO) positron emission tomography (PET). However, conv...
Neuroinflammation is a hallmark of numerous neurodegenerative, psychiatric, and chronic pain disorders and can be assessed in vivo with 18 kDa translocator protein (TSPO) positron emission tomography (PET). However, conventional quantification methods of TSPO PET are limited and often overlook the spatial relationships between regional signals. The application of network-based approaches to TSPO PET imaging may provide a novel framework to capture disease-specific neuroinflammatory patterns. To address this question, here we developed a data-driven, network-based approach to generate individual brain-wide TSPO PET matrices, employing Euclidean distance to quantify inter-regional pharmacokinetics similarity. We applied this approach to a large multicenter dataset of 528 PET scans utilizing three different TSPO tracers ([11C]-PBR28, [18F]-DPA714, [11C]-PK11195), including healthy controls and patients with different diseases such as multiple sclerosis, traumatic brain injury, schizophrenia, depression, and chronic low back pain. Statistical modelling and machine learning classifiers were applied to evaluate the impact of experimental and biological factors on TSPO similarity patterns and to investigate their potential for capturing disease-specific signatures. TSPO similarity patterns demonstrated high biological specificity and reproducibility, with strong test–retest correlations (mean Spearman’s ρ = 0.84). Average precision of disease classification exceeded chance performance by 23–89% across conditions and was driven by condition-specific regional hubs whose topological distributions closely mirrored disease pathophysiology. This specificity was further supported by minimal overlap in feature importance values across conditions. Altogether, our findings show that network-based analysis of human TSPO PET data can detect disease-specific neuroinflammatory signatures. Such methodologies underscore the biological significance of TSPO PET and enhance its translational value, supporting precision medicine strategies for neuroinflammatory disorders.
Single-cell and spatial transcriptomics analyses reveal tumor microenvironment-driven proliferation of NF2-associated vestibular schwannomas.
Wang Y, Xu G, Ren Y … +13 more , Pan T, Zhang Y, Liu Y, Yang Z, Zhao Z, Li P, Yan M, Zhang C, Wang B, Ma X, Li Y, Xu J, Liu P
J Neuroinflammation · 2026 Apr · PMID 41957607 · Full text
The tumor microenvironment (TME) is crucial for tumor formation and progression, but its specific impact on NF2-related tumors has not been well described. The aim of this study was to analyze the differences in the TME...
The tumor microenvironment (TME) is crucial for tumor formation and progression, but its specific impact on NF2-related tumors has not been well described. The aim of this study was to analyze the differences in the TME among NF2-related schwannomatosis (NF2-SWN) patients with different clinical phenotypes, explore the reasons for these differences, and identify targets for treatment while gaining a deeper understanding of the pathogenesis of the disease. 20 vestibular schwannomas (VSs) from 20 clinically diagnosed NF2-SWN patients, including 11 milder patients (Gardner) and 9 severe patients (Wishart), were analyzed. Single-cell sequencing, TCR sequencing, spatial transcriptomics analysis, multiplex immunofluorescence, immunohistochemistry, and cell experiments were performed to compare the TME of Gardner and Wishart and to elucidate the mechanisms underlying these differences. Our results revealed that NF2-VS consist of 12 significant cell subpopulations, with Gardner and Wishart presenting distinct TME. Wishart exhibited more pronounced immune suppression. Conversely, CD8+ T cells from Gardner demonstrated potential for clonal proliferation. In macrophages, a subtype exhibited higher capacity of angiogenesis and high inflammatory cytokine activity was identified in Wishart, suggested its role in promoting tumor progression. Moreover, we found fibroblasts in Wishart showed excessive stromal deposition, potentially indicated the existence of immunologic barrier. Receptor‒ligand pair analysis revealed that Schwann cells in Wishart regulate immune cell activity via pleiotrophin (PTN), PTN positivity promotes anti-inflammatory cytokine activity, contributing to the formation of an immunosuppressive microenvironment to promote tumor progression. In summary, our study provides an in-depth analysis of the TME of NF2-VS, revealing the differences between Wishart and Gardner. Our study explains how Schwann cells influence the immune landscape to promote tumor development and clarifies the role of the TME in NF2-SWN progression, establishing a theoretical and experimental foundation for future immunotherapeutic strategies for NF2-SWN.
Single-cell omics and flow cytometry identify distinct immune states of dural and brain-infiltrating IL-17-producing γδ T cells after experimental stroke.
Zha M, Jander A, Cai H … +5 more , Piepke M, Degenhardt K, Winter L, Magnus T, Gelderblom M
J Neuroinflammation · 2026 Apr · PMID 41952178 · Full text
BACKGROUND: γδ T cells boost inflammatory responses and exacerbate tissue damage after ischemic stroke. However, the origin, dynamics, and tissue adaptation of γδ T cells in the ischemic brain and its border regions rema...
BACKGROUND: γδ T cells boost inflammatory responses and exacerbate tissue damage after ischemic stroke. However, the origin, dynamics, and tissue adaptation of γδ T cells in the ischemic brain and its border regions remain poorly understood. A systematic integration of large-scale datasets is urgently needed. Here, we investigated the impact of ischemic stroke on the state of meningeal and brain-infiltrating γδ T cells and explored their potential contributions to post-stroke inflammation. METHODS: We conducted an integrated analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets, which included meningeal and brain-infiltrating Ptprc+ (CD45+) immune cells following experimental stroke. γδ T cells were identified and subsequently classified into distinct subtypes through data integration and reference mapping. Subtype-specific functions, tissue residency signatures, migratory programs, and the cellular interactions between γδ T cells and endothelial cells or fibroblasts in the dura and brain were investigated, respectively. Key findings were validated by flow cytometry and immunofluorescence assays in vivo. RESULTS: On day 2 post-experimental stroke, the number of parenchymal γδ T cells significantly increased while dural γδ T cells decreased. The majority of γδ T cells residing in the meninges and infiltrating the brain, both under homeostatic conditions and following stroke, were Rorc⁺ and belonged to the Vγ6⁺ γδ17 cell subset. Compared to dural γδ T cells, brain-infiltrating γδ T cells showed reduced tissue residency capacities, higher migratory pathway activation, and lower Ki‑67 positivity, indicating acute recruitment. In contrast, dural γδ T cells exhibited greater IL‑17-producing capacities on day 3. Redistributions of dural γδ T cells were analyzed, and immunofluorescence revealed a close spatial association between dural γδ T cells and CD31+ cells. Cell–cell communication analysis predicted increased interactions between γδ T cells and CD45− cells in both the dura and the brain. CONCLUSION: Our data indicate that most meningeal and brain-infiltrating γδ T cells after stroke share an activated γδ17 phenotype but display compartmentalized dynamics in activation, proliferation, and migration. These results establish a foundation for further studies on the spatially distinct roles of γδ T cells in post-stroke immunity.
Hypothalamic arcuate microglia in sepsis: AgRP circuit engagement and ARHGAP24-dependent remodeling.
Che M, Feng Z, Xu W … +14 more , Ling X, Zhou M, Peng J, Wu G, Li K, Peng J, Yung KKL, Zhang Z, Wang H, Cai Y, Liang X, Zhang X, Qi S, Ou Y
J Neuroinflammation · 2026 Apr · PMID 41947164 · Full text
BACKGROUND: Sepsis remains a leading cause of death in intensive care, and effective therapies that restore host adaptation are limited. The hypothalamus is a central hub that coordinates endocrine and immune homeostasis...
BACKGROUND: Sepsis remains a leading cause of death in intensive care, and effective therapies that restore host adaptation are limited. The hypothalamus is a central hub that coordinates endocrine and immune homeostasis, yet how defined hypothalamic microcircuits are engaged in sepsis induced neuroimmune dysregulation is poorly understood. Within the hypothalamus, the arcuate nucleus lies adjacent to the fenestrated median eminence, placing microglia close to circulating inflammatory cues, but how these cells respond during systemic inflammation remains unclear. METHODS: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). Arcuate microglial responses were evaluated by immunofluorescence, confocal and electron microscopy, acute slice live imaging, and transcriptomic profiling of the mediobasal hypothalamus using Smart-seq2 of sorted microglia and 10× single-nucleus RNA sequencing (snRNA-seq) with bioinformatic analyses. Microglia were depleted using a Tmem119 driven diphtheria toxin strategy. AgRP neuronal activity was assessed by c-Fos staining, whole-cell patch clamp recordings, and synaptic analysis. AgRP neurons were manipulated by chemogenetics. Sepsis outcomes were assessed by survival, clinical scores, systemic cytokines, endocrine hormones, and open field behavior. ARHGAP24 function was tested by lentiviral knockdown in LPS stimulated BV2 microglia, and Rac1 and Cdc42 signaling was pharmacologically modulated in vitro and via third ventricle delivery in vivo. RESULTS: CLP rapidly activated arcuate microglia and this activation persisted, accompanied by cytoskeletal remodeling and increased motility. AgRP neurons underwent sustained hyperexcitability after CLP, showing increased firing at both 1 day and 7 days with stage specific electrophysiological remodeling. Microglial depletion reduced AgRP activation, worsened sepsis severity, blunted corticosterone release, impaired inflammatory resolution, and compromised open field performance. Chemogenetic manipulation indicated that AgRP activity tracked sepsis outcomes independent of feeding behavior. snRNA-seq of the mediobasal hypothalamus revealed enhanced microglia-AgRP communication after CLP and identified Arhgap24 as a microglial state associated regulator induced along the activation trajectory. Arhgap24 knockdown enhanced microglial protrusive remodeling and amplified LPS induced cytokine responses. Pharmacological inhibition of Rac1 and Cdc42 using AZA1 restrained microglial remodeling and improved sepsis outcomes, whereas pathway activation using CN02 exacerbated these responses. CONCLUSION: Arcuate microglia act as central neuroimmune sensors that couple systemic inflammation to sustained functional remodeling of AgRP neurons, thereby linking sepsis to endocrine and behavioral adaptation. ARHGAP24 restrains Rac1/Cdc42 dependent cytoskeletal remodeling in microglia, maintains an adaptive microglial state, and shapes sepsis outcomes.
Integrative imaging and transcriptomics implicate neutrophils in microvascular no-reflow after stroke.
Abbasi-Habashi S, Clarke M, Ma Y … +4 more , Real MGC, Siegers GM, Jickling GC, Winship IR
J Neuroinflammation · 2026 Apr · PMID 41947154 · Full text
BACKGROUND: Ischemic stroke is a leading cause of adult disability and death, yet recanalization therapies that reopen occluded large arteries benefit only a subset of patients. Stroke patients can experience poor outcom...
BACKGROUND: Ischemic stroke is a leading cause of adult disability and death, yet recanalization therapies that reopen occluded large arteries benefit only a subset of patients. Stroke patients can experience poor outcomes due to recanalization failure or the no-reflow phenomenon, where inflammation and microvascular obstructions prevent effective reperfusion despite successful large-vessel reopening. We hypothesized that failure of collateral and microcirculatory flow is a critical factor underlying the incongruity between large-vessel recanalization and effective tissue reperfusion. Neutrophils, as early responders to ischemic injury, are prime mediators of microvascular dysfunction. To test this, we investigated whether targeted depletion of neutrophils could preserve microvascular flow, improve perfusion, and attenuate inflammatory responses in stroke. MAIN BODY: Using a mouse model of middle cerebral artery occlusion, we applied a double-antibody depletion strategy to achieve efficient and specific removal of circulating neutrophils. This multi-modal study integrated high-resolution intravital imaging of cerebral blood flow and cellular dynamics, cytokine assays, transcriptomic profiling, and infarct size measurements. Neutrophil depletion preserved cortical perfusion (~ 30% vs. ~ 60% reduction in untreated mice), reduced capillary stalls, and nearly doubled early post-reperfusion capillary flow (red blood cell flux ~ 72% vs. ~ 33%). Infarct volumes were modestly reduced, with the most pronounced benefit in aged and female cohorts. Transcriptomic profiling revealed broad suppression of neutrophil-driven inflammatory programs (including Il1b, Mmp8, Lcn2, Tlr2, and Cd14), while protective homeostatic signals (such as Mef2c) were maintained and delayed pro-inflammatory activation (Itgam, Txnip, Tlr13) was prevented. Cytokine assays supported a dampened systemic inflammatory response following neutrophil depletion. CONCLUSIONS: These findings identify neutrophils as central drivers of microvascular failure in acute stroke and support their therapeutic targeting to enhance reperfusion and limit inflammation. The use of a double-antibody depletion strategy underscores both the mechanistic importance of neutrophils and the translational potential of precise immune-modulatory interventions. Our multi-modal approach provides comprehensive insight into immune-vascular interactions after stroke and highlights a translationally relevant strategy for improving outcomes following recanalization therapies.
Endothelial-specific Ezh2 deficiency exacerbates blood-brain barrier dysfunction and neuroinflammation in sepsis-associated encephalopathy.
Zhu H, Sun Q, Wang Y … +18 more , Hu X, Pan Y, Huang T, Xu S, Mu L, Wang Y, Tong M, Tang Y, Luo Z, Yang B, Hou M, Chen Y, Chen Y, Su X, Xu X, Wang Z, Cao M, Xue C
J Neuroinflammation · 2026 Apr · PMID 41947152 · Full text
Sepsis-associated encephalopathy (SAE) is a frequent yet insufficiently understood form of acute brain dysfunction driven by systemic inflammation and neurovascular injury. Here, we identify endothelial Enhancer of Zeste...
Sepsis-associated encephalopathy (SAE) is a frequent yet insufficiently understood form of acute brain dysfunction driven by systemic inflammation and neurovascular injury. Here, we identify endothelial Enhancer of Zeste Homolog 2 (Ezh2) as a key epigenetic regulator that maintains blood-brain barrier (BBB) integrity and restrains neuroinflammatory responses during sepsis. Using constitutive and inducible endothelial-specific Ezh2 knockout mice, we demonstrate that loss of Ezh2 disrupts neurovascular unit organization at baseline, characterized by reduced tight junction protein expression, diminished glucose transporter levels, altered vascular morphology, and impaired astrocytic endfoot coverage. Following cecal ligation and puncture, Ezh2-deficient mice exhibited markedly increased mortality, exacerbated cerebral edema, and severe albumin extravasation, indicating profound BBB breakdown. Neuropathological analyses revealed region-dependent neuronal degeneration and apoptosis across cortex, midbrain, and hippocampus, accompanied by reactive gliosis and microglial activation. The absence of Ezh2 further promoted robust leukocyte infiltration, including neutrophils and CD4⁺/CD8⁺ T cells, into the cortex, basal ganglia, and choroid plexus, consistent with dysregulated peripheral-central nervous system (CNS) immune communication. Transcriptomic profiling identified upregulation of inflammatory, cytokine, and cell death pathways alongside downregulation of synaptic, metabolic, and neuronal maturation programs, providing a mechanistic molecular landscape linking endothelial epigenetic dysfunction to CNS vulnerability. Collectively, these findings reveal that endothelial Ezh2 acts as a protective neurovascular gatekeeper that limits systemic inflammatory penetration into the CNS and mitigates neuroimmune activation during sepsis. This work establishes an epigenetic axis coupling BBB dysfunction to neuroinflammation in SAE and suggests that endothelial-targeted epigenetic modulation may represent a therapeutic strategy for limiting CNS injury in systemic inflammatory disorders.
A novel humanized mouse model exhibits neurobehavioral impairments and recapitulates key neuropathological features of infantile Tay-Sachs disease.
Elbakr L, Forguson G, Truong HA … +8 more , Hung JE, Chan WS, Kim DK, Brewer RA, Steiman S, Nguyen TQ, Vincent A, Ivakine EA
J Neuroinflammation · 2026 Apr · PMID 41947150 · Full text
Tay-Sachs disease (TSD) is a fatal lysosomal storage disorder caused by mutations in the HEXA gene which impair B-hexosaminidase A activity and result in the toxic accumulation of GM2 gangliosides. Here, we report the ge...
Tay-Sachs disease (TSD) is a fatal lysosomal storage disorder caused by mutations in the HEXA gene which impair B-hexosaminidase A activity and result in the toxic accumulation of GM2 gangliosides. Here, we report the generation of a novel mouse model that harbors a partially humanized Hexa gene carrying c.1278insTATC, the most prevalent TSD-causing variant, and a Neu3 deficiency to circumvent a murine bypass pathway. Upon characterization, this model reflects key pathological features of TSD including significant GM2 deposition in the central nervous system (CNS), prominent astrogliosis, neuroinflammation, and exhibit progressive neurobehavioral impairments. Retinal characterization revealed widespread GM2 accumulation leading to structural changes detectable by optical tomography coherence and fundus imaging, highlighting the significance of retinal involvement in TSD. Taken together, these findings establish this model as a valuable tool for elucidating TSD pathophysiology and provides a platform for evaluating targeted therapeutic strategies in a genetically accurate and clinically relevant context.
Activation of the NR3C1-STAT3-SLC6A2 signaling axis by a cyanidin-3-O-glucoside-enriched anthocyanin preparation attenuates neuroinflammation and pain hypersensitivity in intervertebral disc degeneration.
Xue B, Qiu GL, He P … +27 more , Chen RF, Duan W, Gao L, Chen L, Wang CZ, Yu TH, Chen CL, Tang WP, Shi TT, Mao WB, Wang H, Hong Y, Feng S, Shi XY, Ding FF, Ke J, Wang Y, Zhuang L, Luan QQ, Xu WY, Wang LN, Xu JF, Tu YL, Chen GJ, Cai HB, Wang XX, Cai Q
J Neuroinflammation · 2026 Apr · PMID 41943069 · Full text
BACKGROUND: IVDD is a major global health burden and a leading cause of chronic low back pain, yet disease-modifying therapies remain limited. Anthocyanins are natural anti-inflammatory compounds with potential neuroprot...
BACKGROUND: IVDD is a major global health burden and a leading cause of chronic low back pain, yet disease-modifying therapies remain limited. Anthocyanins are natural anti-inflammatory compounds with potential neuroprotective activity, but their roles in IVDD-related neuroinflammation and nociceptive sensitization are unclear. METHODS: Anthocyanins used in this study were a commercially standardized preparation (≥ 98% purity), in which cyanidin-3-O-glucoside (C3G) constituted the predominant component as confirmed by LC–MS analysis. IVDD was established by needle puncture in rats and conditional Cre–loxP mice. Mechanical and thermal pain behaviors were assessed, and disc pathology was evaluated by imaging and histological/biochemical analyses. IL-1β–stimulated NP cultures and NP–DRG co-cultures were used to model neuron–disc interactions. Mechanistic studies combined pharmacological modulation and genetic targeting of NR3C1/STAT3 with assays of NR3C1 nuclear translocation, NR3C1–STAT3 interaction, and STAT3 binding to the SLC6A2 promoter. RESULTS: Cyanidin-3-O-glucoside (C3G)–enriched anthocyanin preparation reduced IVDD-associated neuroinflammation and pain hypersensitivity, improved disc degeneration, and decreased NP apoptosis and inflammatory mediator release. Mechanistically, anthocyanins activated the NR3C1–STAT3–SLC6A2 axis, enhancing NR3C1 nuclear localization, promoting NR3C1–STAT3 coupling, and restoring SLC6A2 expression in sensory neurons. Disrupting NR3C1 or STAT3 weakened these protective and antinociceptive effects. CONCLUSIONS: C3G-enriched anthocyanins alleviate IVDD-related neuroinflammation and pain primarily via the NR3C1–STAT3–SLC6A2 signaling axis.
Brain endothelial PTPRO drives LPS-induced metabolic reprogramming and neuroinflammation in sepsis-associated encephalopathy.
Wu F, Tang H, Jia H … +16 more , Li C, Song Y, Hu J, Cao H, Zhang B, Zhang X, Jiang H, Pan Z, Zhou W, Gou Z, Li T, Li T, Wang H, Wang H, Qian Z, Wang T
J Neuroinflammation · 2026 Mar · PMID 41906129 · Full text
BACKGROUND: Sepsis-associated encephalopathy (SAE) is characterized by profound neuroinflammation and blood–brain barrier (BBB) disruption, yet the molecular mechanisms linking endothelial metabolic reprogramming to neur...
BACKGROUND: Sepsis-associated encephalopathy (SAE) is characterized by profound neuroinflammation and blood–brain barrier (BBB) disruption, yet the molecular mechanisms linking endothelial metabolic reprogramming to neuroinflammatory responses remain poorly defined. Protein tyrosine phosphatase receptor type O (PTPRO) has been implicated in endothelial signaling; however, its role in metabolic and inflammatory dysregulation during SAE is unknown. METHODS: We analyzed transcriptomic responses to lipopolysaccharide (LPS) challenge in control and PTPRO-silenced brain microvascular endothelial bEND.3 cells to define the impact of PTPRO on endothelial gene expression under septic stress. Endothelial cells with PTPRO overexpression, siRNA-mediated knockdown, or pharmacologic inhibition were assessed for glycolytic activity, glucose uptake, HIF-1α signaling, BBB integrity, and inflammatory responses following LPS exposure. LPS-induced neuroinflammation models were established in wild-type, systemic PTPRO knockout (PTPRO⁻/⁻), and endothelial-specific PTPRO conditional knockout (E-cKO) mice, and disease severity was systematically evaluated. RESULTS: We provide the first evidence that PTPRO regulates LPS-induced glycolytic pathways at the transcriptomic level. PTPRO silencing or inhibition in bEND.3 cells significantly attenuated LPS-induced glycolytic activation, HIF-1α accumulation, glucose transporter translocation, and lactate production. In vivo, LPS-induced neuroinflammation was associated with enhanced glycolysis, increased HIF-1α expression, BBB disruption, and elevated neuroinflammatory cytokine production; these effects were markedly reduced in both systemic and conditional endothelial-specific PTPRO-deficient mice, with preservation of BBB integrity and decreased neutrophil infiltration. Mechanistically, PTPRO modulated ErbB2 phosphorylation at multiple tyrosine residues and activated AKT–mTOR signaling under inflammatory conditions, linking PTPRO to endothelial glycolytic reprogramming and inflammatory activation. Pharmacologic inhibition of HIF-1α or glycolysis suppressed pro-inflammatory cytokine production, indicating that PTPRO promotes endothelial inflammation through a HIF-1α–dependent glycolytic pathway. CONCLUSIONS: PTPRO drives endothelial glycolytic reprogramming and neuroinflammation in LPS-induced neuroinflammation by regulating HIF-1α signaling through the ErbB2–AKT–mTOR axis. Targeting PTPRO confers metabolic, neurovascular, and anti-inflammatory protection, highlighting PTPRO as a promising therapeutic target for SAE.
TNF-α impairs the stria vascularis by inducing pericyte apoptosis via the NF-κB pathway in gentamicin-induced hearing loss.
Li G, Chen G, Hu R … +4 more , Zeng J, Liu P, Liang M, Zheng Y
J Neuroinflammation · 2026 Mar · PMID 41904538 · Full text
Aminoglycoside antibiotics remain crucial for the treatment of severe infections caused by multidrug-resistant bacteria; however, their clinical use is limited by the risk of irreversible hearing loss. Previous studies h...
Aminoglycoside antibiotics remain crucial for the treatment of severe infections caused by multidrug-resistant bacteria; however, their clinical use is limited by the risk of irreversible hearing loss. Previous studies have primarily attributed aminoglycoside-induced hearing loss to cochlear hair cell loss and subsequent spiral ganglion degeneration, while the contribution of the stria vascularis remains unclear. In the present study, we demonstrate that gentamicin administration induces apoptosis of stria vascularis pericytes, leading to stria vascularis dysfunction and consequent hearing loss in mice. Mechanistically, gentamicin exposure activated macrophages within the stria vascularis and significantly increased local expression of tumor necrosis factor-α (TNF-α). In vitro, we found that TNF-α triggered stria vascularis pericyte apoptosis via activation of the NF-κB signaling pathway. Importantly, in vivo pharmacological blockade of TNF-α with infliximab (IFX) or inhibition of NF-κB signaling with JSH-23 effectively preserved pericyte survival, attenuated stria vascularis damage, and mitigated gentamicin-induced hearing loss in mice. Collectively, these findings uncover TNF-α/NF-κB-dependent vascular-inflammatory mechanism underlying gentamicin ototoxicity and identify stria vascularis pericytes as a novel and druggable therapeutic target for the prevention of gentamicin-induced hearing loss.
Lysosomal cholesteryl ester hydrolysis drives white matter repair by reprogramming microglia into a novel reparative state.
Hu Y, Tang K, Hu H … +10 more , Mi H, Li X, Wang H, Liu J, Xia Y, Huang W, Kirchhoff F, Xiao GD, Jia J, Cheng J
J Neuroinflammation · 2026 Mar · PMID 41904522 · Full text
White matter repair relies on microglial clearance of cholesterol-rich myelin debris. Microglia have been reported to predominantly depend on de novo sterol synthesis to support this repair process. Lysosomal acid lipase...
White matter repair relies on microglial clearance of cholesterol-rich myelin debris. Microglia have been reported to predominantly depend on de novo sterol synthesis to support this repair process. Lysosomal acid lipase (LAL) is the only known lysosomal enzyme capable of hydrolyzing cholesterol esters. In stark contrast to previous studies, we demonstrate here that LAL-mediated lysosomal lipolysis—not de novo sterol synthesis—serves as a central determinant of the microglial capacity to drive white matter repair. Using single-cell RNA sequencing, we identified a novel reparative microglial state characterized by simultaneously high expression of glycoprotein nonmetastatic melanoma protein B (GPNMB) and LAL. Following white matter injury, GPNMB+ microglia expanded and constituted the major microglial subset responsible for myelin debris engulfment. However, GPNMB+ microglia displayed context-dependent capacity to digest internalized myelin debris and mediate remyelination, with marked differences between reparable white matter injury and nonregenerative injury induced by white matter stroke (WMS). Transcriptomic profiling identified LAL as a key regulator of the reparative phenotype in GPNMB+ microglia. Independent of cytosolic lipases—widely regarded as synergistic mediators of LAL in cholesteryl ester hydrolysis, microglial LAL was both indispensable for myelin debris clearance and spontaneous remyelination in the reparable injury model, and sufficient to restore these processes following WMS-induced irreparable white matter injury. Mechanistically, LAL-mediated lysosomal lipolysis constituted the primary pathway for cholesteryl ester hydrolysis in microglia after white matter injury. This pathway converted cholesteryl esters into free cholesterol and activates liver X receptors (LXRs), both of which were required to reprogram microglial into the reparative state. Consistently, LXR activation alone was insufficient to rescue defective white matter repair caused by LAL deficiency. Hydroxypropyl-β-cyclodextrin (HβCD), an FDA-approved drug carrier, effectively lowers intracellular cholesterol levels through incompletely defined mechanisms. HβCD specifically upregulated LAL expression within white matter lesions and promoted remyelination via a LAL-dependent manner following WMS, supporting its potential as a therapeutic agent for WMS. Collectively, this study identifies lysosomal cholesterol ester hydrolysis as a novel therapeutic target for the treatment of irreversible white matter injury.
Alternatively activated neutrophils limit T cell-driven neuroinflammation.
Atkinson JR, Bellinger C, Jerome AD … +11 more , Gardner AM, Groover HK, Chen S, Moffatt AM, Sepeda JA, Dokiburra A, Hammond LA, Liu T, Webb A, Sas AR, Segal BM
J Neuroinflammation · 2026 Mar · PMID 41896962 · Full text
OBJECTIVE: Non-canonical myeloid cell populations are increasingly recognized as critical regulators of inflammation in neuroimmunological disease. Here, we investigate the role of alternatively activated neutrophils (aa...
OBJECTIVE: Non-canonical myeloid cell populations are increasingly recognized as critical regulators of inflammation in neuroimmunological disease. Here, we investigate the role of alternatively activated neutrophils (aaN) in limiting encephalitogenic T cell responses during experimental autoimmune encephalomyelitis (EAE), a widely used model of multiple sclerosis. METHODS: Arginase-1–expressing aaN were identified and characterized within central nervous system (CNS) infiltrates during EAE using flow cytometry, single-cell RNA sequencing, and fluorescent in situ hybridization (RNAscope) combined with immunohistochemistry. The immunomodulatory properties of aaN were evaluated in vitro using CD4⁺ T cell suppression assays and in vivo by adoptive transfer of ex vivo–generated aaN during the preclinical phase following encephalitogenic T-cell injection. RESULTS: aaN were consistently detected within the CNS throughout EAE and spatially co-localized with encephalitogenic T cells. Transcriptomic profiling of aaN revealed enrichment of pathways associated with regulation of T cell activation and immune suppression. CNS-derived aaN potently inhibited CD4⁺ T cell proliferation in vitro. Therapeutic augmentation of this population, via adoptive transfer of ex vivo–generated aaN into mice following the injection of encephalitogenic T cells, delayed clinical EAE onset, markedly reduced the accumulation of pathogenic T cells within CNS lesions, and significantly enhanced neuronal survival. Mechanistically, ex vivo–generated aaN suppressed T cell responses through a contact-dependent, PD-L1–independent pathway, indicating a previously unrecognized mode of neutrophil-mediated immunoregulation. INTERPRETATION: These findings identify aaN as a previously underappreciated immunoregulatory population within the inflamed CNS that restrains pathogenic T cell responses and limits neuroinflammation during EAE. Collectively, our data support the therapeutic potential of strategies that augment aaN activity, including autologous aaN-based cell therapy or interventions that promote CNS homing, polarization, and persistence of endogenous aaN, as novel approaches for disease modification in multiple sclerosis.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe