Journal of Neuroinflammation最新文献

{"title":"CX3CL1/CX3CR1-dependent microglial phagocytosis of oligodendrocyte precursor cells contributes to sevoflurane-induced myelination impairments in neonatal mice.","authors":"Jiangming Lv, Zhangting Xia, Xin Wang, Ping Zhao, Ziyi Wu","doi":"10.1186/s12974-026-03997-8","DOIUrl":"10.1186/s12974-026-03997-8","url":null,"abstract":"<p><p>General anesthesia exposure in early life may disrupt the normal progression of developmental myelination, but the underlying mechanisms remain unclear. Early postnatal microglia in developing white matter exhibit diverse transcriptional and functional states, including a population with pronounced phagocytic activity. This study aims to investigate whether sevoflurane impairs oligodendrocyte myelination by promoting microglial phagocytosis of oligodendrocyte precursor cells (OPCs). Mice received either a single 2-h exposure to 3.3% sevoflurane on postnatal day 2 (P2) or repeated 2-h exposures on P2, P3, and P4. Neurobehavioral tests were used to assess cognitive and fine motor functions. The effects of microglial phagocytosis of OPCs on cerebral myelination were assessed using three-dimensional reconstruction and related biochemical analysis. Our findings indicate that repeated sevoflurane exposure, rather than a single exposure, induced hypomyelination and was associated with persistent cognitive and fine motor deficits. Repeated sevoflurane exposures promoted microglial activation and excessive phagocytosis of OPCs, thereby decreasing the number of oligodendrocytes and impairing developmental myelination. Mechanistically, repeated sevoflurane exposure enhanced CX3CL1/CX3CR1 signaling in neonatal brain tissue. In cultured microglial cells, sevoflurane altered Rac1-related cytoskeletal regulation and increased phagocytic activity. CX3CR1 knockout attenuated the phagocytic ability of microglia and rescued oligodendrocyte myelination and neurobehaviors. This study indicates that CX3CL1/CX3CR1-dependent microglial phagocytosis of OPCs might contribute to sevoflurane-induced myelination impairments in neonatal mice, and provides a potential therapeutic target for preventing anesthesia-induced developmental neurotoxicity.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCL10 contributes to female-specific pathological progression in tauopathy model mice.","authors":"Ryohei Uenishi, Rinna Kawata, Tatsuya Manabe, Yukio Matsuba, Naomi Mihira, Toru Takeo, Takaomi C Saido, Masanori Hijioka, Takashi Saito","doi":"10.1186/s12974-026-03989-8","DOIUrl":"10.1186/s12974-026-03989-8","url":null,"abstract":"<p><p>Neuroinflammation plays a central role in the progression of tauopathy via the glial activation and T cell accumulation in the brain parenchyma. However, the key molecular mediators that link these processes to tau pathology remain poorly understood.Here, we identify C-X-C motif chemokine ligand 10 (CXCL10) as a critical inflammatory mediator that is markedly upregulated in the brains of P301S-mutant tau transgenic mice and associated with regions of severe tau pathology. Spatial transcriptomics revealed that CXCL10 is mainly expressed by disease-associated astrocytes, defining an astrocytic CXCL10-rich inflammatory niche within the tauopathy brain.Genetic ablation of Cxcl10 significantly attenuated soluble and insoluble tau accumulation selectively in 9-month-old female mice, whereas no attenuation of tau accumulation was observed at 11-12 months of age. In addition, Cxcl10 deficiency significantly prolonged survival specifically in female tauopathy mice. Although Cxcl10 deficiency reduced the number of parenchymal T cells in both sexes, this reduction did not explain the female-specific effects. Furthermore, Cxcl10 deficiency did not alter neurodegeneration and motor dysfunction, suggesting that downstream sex-dependent regulatory mechanisms govern tauopathy progression. Moreover, CXCL10-dependent inflammatory activation within the local microenvironments was observed in both sexes. Although the molecular mechanisms underlying the sex-dependent effects of CXCL10 remain unclear, these findings suggest that CXCL10 contributes to tau pathology through multiple inflammatory pathways.In summary, our findings identify CXCL10 as a key inflammatory mediator of sex specific tau-associated pathology.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroinflammation-associated thalamocortical functional connectivity and cognition in older adults.","authors":"Jeffrey Browndyke, Tyler Reekes, Mary C Wright, Melody R Smith, Michael Devinney, Piper Boykin, Vinith R Upadhya, Daphne Zhu, Katherine T Martucci, Leslie M Shaw, Teresa Waligorska, Charlotte Herber, Connie Tian Yu, Henrik Zetterberg, Kaj Blennow, Janet L Huebner, Harvey J Cohen, Heather Whitson, Joseph P Mathew, Miles Berger","doi":"10.1186/s12974-026-03962-5","DOIUrl":"10.1186/s12974-026-03962-5","url":null,"abstract":"<p><p>Neuroinflammation has detrimental neurocognitive effects in patients with systemic and neuropsychiatric diseases. Yet, outside of these conditions, it is unclear to what extent neuroinflammation modulates brain network-level function in older adults in the general population and, what, if any cognitive performance issues arise as a result. To evaluate these questions, we compared cerebrospinal fluid (CSF) inflammatory cytokine levels, resting-state functional magnetic resonance imaging, and cognitive performance data in 96 community-dwelling older adults (age ≥ 60 yrs). Principal component analysis yielded three components, accounting for > 50% of the variance in CSF cytokine levels; of which, the first principal component (PC1) accounted for 32% of the overall variance. A multivariate pattern analysis regression model, adjusted for age, sex and in-scanner movement, revealed cytokine PC1 values were inversely associated with functional connectivity between the mediodorsal thalamus and multiple cortical regions associated with the frontoparietal, default mode and dorsal attention functional brain networks (p-FWE = 0.037). For the majority of these cortical regions, functional connectivity with the mediodorsal thalamus was not associated with cognitive performance. In a robust multivariable model, narrative memory performances were positively associated with thalamocortical connectivity to a posterior parietal hub region of the frontoparietal and dorsal attention networks [beta = 0.25 (95% CI; 0.01, 0.49); p = 0.040], but this association did not survive correction for the number of evaluated cognitive domains (Bonferroni-adjusted p < 0.01). Study results reveal that neuroinflammatory CSF cytokine levels were inversely associated with functional connectivity between the mediodorsal thalamus and cortical regions largely involved in frontoparietal, dorsal attention and default mode networks, but the functional consequences of this relationship remain to be determined and will require further investigation to determine if reduced corticothalamic functional connectivity may help account, in part, for common illness-related cognitive complaints.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13570534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copine-5-IgG-related autoimmune encephalitis: a novel paraneoplastic neurological syndrome with a strong melanoma association.","authors":"Matthias Elstner, Sven Jarius, Brigitte Wildemann, Katharina Drüschler, Kathrin Borowski, Bianca Teegen, Corinna Bien, Janek Nagel, Ilka Kleffner, Markus Höltje, Jürgen Haas, Klemens Ruprecht, Yvonne Müller, Christiane Radzimski, Lars Komorowski, Ramona Miske, Madeleine Scharf","doi":"10.1186/s12974-026-03793-4","DOIUrl":"10.1186/s12974-026-03793-4","url":null,"abstract":"<p><strong>Background: </strong>Although significant progress has been made in identifying antigen targets in autoimmune encephalitis (AIE), in a substantial proportion of patients with presumed AIE no known autoantibodies can be detected. Herein, we describe a novel autoantibody reactivity, directed against copine-5 (CPNE5), in patients with AIE and melanoma.</p><p><strong>Methods: </strong>Patients were identified through routine clinical testing for anti-neural autoantibodies by indirect immunofluorescence on neuronal tissue sections. The antigen was identified by immunoprecipitation and mass spectrometry and confirmed by recombinant protein assays.</p><p><strong>Results: </strong>Serum and cerebrospinal fluid (CSF) immunoglobulin G (IgG) from four patients was found to exhibit distinct binding to cerebellar and hippocampal neurons. Copine-5 was identified as the target antigen. Clinical manifestations included cognitive decline, confusion/disorientation, psychosis, seizures and signs and symptoms compatible with basal ganglia involvement (movement disorders, including secondary parkinsonism, and/or abulia/akinetic mutism), alongside pain (including painful tonic spasms and focal allodynia), dysarthria, dysphagia, and abducens nerve palsy. Brain magnetic resonance imaging disclosed hyperintense lesions in the basal ganglia and the temporal lobe. CSF analysis revealed mild pleocytosis, intrathecal IgG synthesis, and blood/CSF barrier dysfunction. Of particular note, all four patients had melanoma, with an occult primary in three. In one patient, melanoma diagnosis and immunotherapy with the anti-PD-1 immune checkpoint inhibitor nivolumab preceded the onset of AIE by 9 months. Glucocorticoid treatment and/or intravenous immunoglobulins led to transient improvement in at least three patients; however, all relapsed and three progressed to hypoactive delirium or mutism. Plasma exchange and cyclophosphamide treatment were followed by clinical improvement and stabilization in one patient, but potentially contributed to fatal infectious complications. Copine-5-IgG belonged to the strongly complement-activating IgG1 subclass and was produced intrathecally. Serum titers ranged between 1:1000 and 1:100,000.</p><p><strong>Conclusions: </strong>Copine-5 is a novel autoantibody target in AIE. Testing for anti-copine-5 autoantibodies should be included in the diagnostic workup of patients with AIE, especially, but not exclusively, if associated with melanoma or positive melanoma-associated tumor markers. Further studies investigating the immunopathogenesis of copine-5-related autoimmunity and the potential significance of anti-copine-5 as a novel paraneoplastic serological marker and of copine-5 as a histopathological tumor marker in patients with suspected melanoma are highly warranted.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13411103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148604216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFN-γ protects the human blood-brain barrier from Toxoplasma gondii-mediated dysfunction via CCL2 suppression.","authors":"Mia C Somenzi, Kameron T Bell, Abigail M Bitters, Collin S Stratton, Samantha R Springston, Kamryn E Zadeii, Rylee J Anderson, Avery V Stanley, Daisy Woellner-Santos, Scott G Canfield, Américo H López-Yglesias","doi":"10.1186/s12974-026-03978-x","DOIUrl":"10.1186/s12974-026-03978-x","url":null,"abstract":"<p><p>The obligate intracellular parasite Toxoplasma gondii infects nearly one-third of the global population, yet its impact on human blood-brain barrier (BBB) function remains poorly defined. In this study, we use human induced pluripotent stem cell-derived (iPSC) brain-like microvascular endothelial cells (BMECs), a physiologically relevant BBB model, to investigate if T. gondii infection directly compromises barrier integrity. We show that infection induces robust monocyte chemotactic protein-1 (also known as CCL2) secretion from BMECs, and that CCL2 itself serves as a previously unrecognized driver of BBB dysfunction. Notably, interferon-gamma (IFN-γ) limits BMEC-derived CCL2 release and protects against parasite-mediated barrier damage. These findings identify an IFN-γ-dependent, BMEC-intrinsic defense mechanism that helps preserve central nervous system (CNS) integrity during infection. Collectively, this work establishes a mechanistic foundation for understanding how T. gondii disrupts the human BBB and reveals a novel protective role for IFN-γ in mitigating CNS barrier dysfunction.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging-enhanced accumulation of fibroblasts excludes oligodendrocytes in demyelinated lesions.","authors":"Brian M Lozinski, George S Melchor, Charlotte D'Mello, Rianne P Gorter, Yifei Dong, Samira Ghorbani, Cenxiao Li, Marlene Morch, Dorsa Moezzi, Rajiv Jain, Parisa Etemadi Nezhad, Chang-Chun Ling, Carlos Camara-Lemarroy, Rui Li, Jeffrey K Huang, V Wee Yong","doi":"10.1186/s12974-026-03976-z","DOIUrl":"https://doi.org/10.1186/s12974-026-03976-z","url":null,"abstract":"<p><p>Fibroblast dysregulation contributes to pathological fibrosis and aberrant repair. Emerging evidence suggest that fibroblasts accumulate in lesions following central nervous system injury, but whether and how they influence oligodendrocyte repair responses, including in aging, is uncertain. Here we report that fibroblasts accumulate in the parenchyma of spinal cord white matter lesions of 6 - 10 week old young mice after lysolecithin-induced demyelination. This was first observed through immunofluorescence microscopy that employed several markers attributed to fibroblasts, including platelet-derived growth factor-β, collagen type 1α1, α-smooth muscle actin, periostin and fibronectin; and by the use of platelet-derived growth factor-β TdTomato reporter transgenic mice. Single-nucleus and spatial transcriptomics of lysolecithin lesions established the presence of fibroblasts in lysolecithin lesions and delineated them from closely related pericytes. CellChat ligand - receptor analyses highlight fibroblasts in the lysolecithin environment as a major source of input of signals for microglia/macrophages and oligodendrocyte precursor cells, with numerous reciprocal interactions. The infiltration of fibroblasts was promoted by microglia/macrophages, as anticipated by their temporal representation in lysolecithin lesions, and by tissue culture experiments where the migration of fibroblasts was enhanced by macrophages. Of particular relevance to spontaneous regenerative events in lysolecithin demyelination, areas of fibroblast accumulation were devoid of oligodendrocyte precursor cells. In tissue culture, oligodendrocyte precursor cells were excluded from fibroblast domains. Moreover, fibroblast accumulation after lysolecithin injury was enhanced with increasing age, a known detriment to the capacity to remyelinate after injury, and exclusion of oligodendrocyte precursor cells from fibroblast areas of 48-52 week mice exceeds that occurring in younger 6-10 weeks animals. Finally, by mining a publicly available single-nucleus RNA database of multiple sclerosis, we found fibroblasts in the edge of chronic active and chronic inactive lesions and in lesion core, and fewer in periplaque or normal white matter. We identified several communication networks between fibroblasts, microglia/macrophages and oligodendrocyte precursor cells in these MS lesions. Our collective results demonstrate a role of fibroblasts in demyelination-associated neuropathology, which is exacerbated by aging, and highlight the importance of regulating fibroblasts to promote effective CNS repair.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCL5 and CD11b-fibrin interactions regulate microglia migration and morphology in hyperinflammatory experimental cerebral malaria.","authors":"Nadia D Domingo, Olivia D Solomon, Paula Villarreal, Florentin Aussenac, Difernando Vanegas, Mark Joseph Endrino, Andrew S Mendiola, Lucinda Puebla-Clark, Komi Gbedande, Astrid E Cardona, Katerina Akassoglou, Matthew J Flick, Gracie Vargas, Robin Stephens","doi":"10.1186/s12974-026-03969-y","DOIUrl":"10.1186/s12974-026-03969-y","url":null,"abstract":"<p><strong>Background: </strong>Microgliosis and severe coagulation, including fibrinogen deposition, are features of both experimental and human cerebral malaria (CM), a lethal disease. Vascular-associated microglia migrate to coagulated cerebral vessels containing inflammatory monocytes and T cells in experimental CM. We previously showed that microglial depletion exacerbates coagulation and disease severity, including hypothermia, while anticoagulant treatment reduces microgliosis and prevents mortality. These data suggest an overall protective effect of microglia on eCM, and indicate a link between microgliosis, hypothermia, and coagulation. Therefore, mechanisms of migration and activation of microglia, T cells, and monocytes were studied in relation to the role of fibrin(ogen) in eCM.</p><p><strong>Methods: </strong>Using both Plasmodium berghei ANKA infection or experimental CM, and P. chabaudi infection of IL-10-deficient mice (IL-10 KO), which causes a hyperinflammatory response including neuropathology, intravital two-photon microscopy and flow cytometry, were used to test patterns and mechanisms of migration. In vivo methods included intranasal administration of CCL5 receptor antagonist Met-CCL5; systemic integrin-blocking antibodies and mutant animals (IL-10 KO, ICAM1 KO), and anticoagulant treatment. Clotting-deficient mice (Fga KO, Fib^AEK) were tested for the absence of fibrinogen in clotting, while fibrinogen γ-chain mutation (Fibγ^390-396 A) mice and intranasal administration of a fibrinogen γ-derived inhibitory peptide (Fibrin γ^377-395), which disrupts CD11b-fibrin interactions, assessed the role of CD11b-fibrin interactions in microglial activation in eCM.</p><p><strong>Results: </strong>Intraluminal adhesion and crawling of CCR2^RFP+ cells, including T cells and inflammatory monocytes, was observed in cerebral vessels; however, there was no evidence that brain adherence of T cells or monocytes depends on classical adhesion molecules or coagulation. Intranasal administration of met-CCL5 reduced both microglial recruitment to vessels and CD8 T cell adherence and fibrin(ogen) deposition. Despite the previously published protective effects of the anticoagulant drug in IL-10 KO, clotting-deficient mice showed no change in P. berghei ANKA mortality. However, disruption of fibrin-CD11b interactions by both genetic and peptide inhibition led to exacerbated hypothermia in both experimental CM models. Reduced microglial hypertrophy also occurred in Fibrin γ^377-395 peptide-treated IL-10 KO mice infected with P. chabaudi.</p><p><strong>Conclusions: </strong>These data support our previous study suggesting that microglia are involved in the regulation of hypothermia in eCM and reveal CCL5 and fibrin-CD11b signaling in microglia as key molecular pathways modulating neuroinflammation in malaria.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148829397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antigen-specific CD8 T cells accumulate and functionally reactivate in the bone marrow following brain infection.","authors":"Delaney M Anani-Wolf, Eliese M Moelker, Shannon E Wallace, Rachael A Reesman, Kelly M Hotchkiss, Kathryn E Blethen, Saskia Hemmers, Christian K Pfaller, Anna L Borchers, Pamela K Norberg, Brittany N Thomas, Michelle L Bowie, Asma Hassani, Michael D Forston, Alexandra M Hoyt-Miggelbrink, Cori E Fain, Vatsal Jain, Mustafa Khasraw, Gerald A Grant, Vidyalakshmi Chandramohan, Aaron J Johnson, Katayoun Ayasoufi","doi":"10.1186/s12974-026-03968-z","DOIUrl":"10.1186/s12974-026-03968-z","url":null,"abstract":"<p><strong>Background: </strong>Bone marrow is a primary immune organ responsible for hematopoiesis, yet its role in shaping adaptive immune responses remains incompletely understood. In particular, whether antigen-specific CD8 T cell responses can arise and persist within the bone marrow following brain infection is unclear.</p><p><strong>Methods: </strong>We used intracranial infection with Theiler's Murine Encephalomyelitis Virus (TMEV) in C57BL/6 mice, along with complementary antigen delivery (OVA + Poly I:C) and systemic infection (LCMV) models. Antigen-specific CD8 T cells were quantified in the brain, secondary lymphoid organs, and bone marrow using tetramer-based flow cytometry. Lymphocyte trafficking was modulated using FTY720, and functional memory responses were assessed via peptide reactivation. Hematopoietic stem and progenitor cell (HSPC) populations and myeloid compartments were analyzed by flow cytometry.</p><p><strong>Results: </strong>Antigen-specific CD8 T cells accumulated in the bone marrow within 5-7 days following intracranial TMEV infection, with kinetics comparable to secondary lymphoid organs. Antigen was detectable in the bone marrow within 24 h of intracranial delivery and was primarily associated with migratory antigen-presenting cells. Antigen-specific CD8 T cells persisted long-term in the bone marrow and demonstrated robust expansion upon antigen re-encounter, even under conditions limiting lymphocyte egress. Reactivation of these cells was associated with expansion of Lineage⁻Sca-1⁺c-Kit⁺ (LSK) HSPCs and increased MHCII⁺ myeloid populations. This increase in the LSKs and MHCII + myeloid cells in the bone marrow niche was abrogated with CD8 T cell depletion.</p><p><strong>Conclusions: </strong>These findings establish the bone marrow as an active site of antigen-specific CD8 T cell accumulation, persistence, and functional reactivation following brain infection. Antigen-specific CD8 T cell activity within the bone marrow is associated with modulation of the hematopoietic niche, highlighting a previously underappreciated link between CNS-directed immune responses and systemic hematopoiesis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SPRY1 suppresses microglial fatty acid oxidation by retaining FATP3 on the endoplasmic reticulum in Alzheimer's disease.","authors":"Yu-Ge Zhang, Shi-Yao Li, Yi-Zhen Hu, Yi Ding, Yu-Tong Zhang, Hui-Wen Zhang, Yong-Jie Zhang, Lu Xu, Zhi-Yuan Zhang, Lei Li","doi":"10.1186/s12974-026-03949-2","DOIUrl":"10.1186/s12974-026-03949-2","url":null,"abstract":"<p><strong>Background: </strong>Microglial metabolic dysfunction is increasingly recognized as a key driver of neuroinflammation in Alzheimer's disease (AD). However, the specific metabolic regulators linking lipid metabolism to pathological activation remain poorly defined.</p><p><strong>Methods: </strong>We performed integrative transcriptomic analysis on four human AD brain datasets to identify core metabolic hubs. Sprouty homolog 1 (SPRY1) expression was examined in human post-mortem tissues, and its functional role was validated in primary microglia, Drosophila, and APP/PS1-21 mice using genetic knockdown, behavioral assays, and histological analysis. Moreover, we employed co-immunoprecipitation, mass spectrometry, and metabolic flux assays to elucidate the underlying pathways.</p><p><strong>Results: </strong>We identified SPRY1 as a key hub gene upregulated in the hippocampus of AD patients and mouse models. SPRY1 was predominantly expressed in plaque-associated microglia, and specifically correlated with advancing age, Aβ load and Braak stage. Functionally, microglial SPRY1 knockdown enhanced Aβ phagocytosis, reduced pro-inflammatory cytokines, and protected neurons from Aβ-induced damage in vitro. In vivo, glial-specific knockdown of the SPRY1 homolog sty rescued cognitive and motor deficits in AD flies, while microglia-specific knockdown in mice reduced amyloidosis and neuroinflammation. Mechanistically, SPRY1 acted as a metabolic switch by retaining fatty acid transport protein 3 (FATP3) on the endoplasmic reticulum (ER). This interaction blocked FATP3 translocation to mitochondria, thereby reducing fatty acid oxidation (FAO) and promoting lipid droplet (LD) accumulation, which drives a microglial pro-inflammatory phenotype.</p><p><strong>Conclusions: </strong>This study unveils a novel SPRY1-FATP3 retention mechanism that links impaired fatty acid metabolism to neuroinflammation. Targeting this axis represents a promising strategy to reprogram microglial metabolism and provide neuroprotection in AD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic mechanisms in traumatic brain injury: a focus on astrocytes and therapeutic implications.","authors":"Lulin Li, Alyssa M Bonfoey, Bryan Sun, Odette A Harris, Jian Luo","doi":"10.1186/s12974-026-03974-1","DOIUrl":"10.1186/s12974-026-03974-1","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) triggers complex molecular and cellular responses that persist well beyond the initial injury. Neuroinflammation is a prominent feature of the post-injury response and a significant contributor to progressive neuronal dysfunction and increased risk of chronic neurodegeneration. Epigenetic mechanisms have emerged as important regulators of the injury response. Astrocytes are increasingly recognized as key mediators of this epigenetic regulation. Injury-induced epigenetic reprogramming in astrocytes may perpetuate maladaptive inflammatory and metabolic states, thereby increasing vulnerability to delayed neurodegeneration. Preclinical studies suggest that pharmacologic or genetic modulation of epigenetic regulators can improve outcomes after experimental TBI. However, clinical translation remains constrained by limited cell-type specificity and potential off-target effects. This review evaluates current evidence on epigenetic regulation after TBI, with an emphasis on astrocyte-centered mechanisms linking acute injury to chronic pathology. We further discuss key translational challenges and highlight emerging precision strategies aimed at cell-type-specific, temporally controlled epigenetic modulation to mitigate long-term neurological consequences.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}