Journal of Neuroinflammation最新文献

{"title":"LncBADR promotes T cell-mediated autoimmunity by binding Mccc1 and Pcca to regulate BCAAs degradation.","authors":"Yanting Lei, Jing Yu, Xinrui Huo, Zhaoying Li, Jing Wang, Yixiang Jiang, Ying Yu, Yan Huang, Wenkang Jiang, Jiangtian Tian, Dan Kong, Yumei Liu, Xijun Liu, Xiujuan Lang, Hulun Li, Bo Sun","doi":"10.1186/s12974-025-03538-9","DOIUrl":"10.1186/s12974-025-03538-9","url":null,"abstract":"<p><p>T cell dysfunction is a pivotal driving factor in autoimmune diseases, yet its underlying regulatory mechanisms remain incompletely understood. The role of long non-coding RNAs (lncRNAs) in immune regulation has gradually been recognized, although their functional mechanisms in T cells remain elusive. This study focuses on lncBADR (LncRNA Branched-chain Amino acids Degradation Regulator), elucidating its mechanism by which it regulates branched-chain amino acids (BCAAs) metabolism to influence T cell effector functions. Mice with specific knockout of lncBADR (T cell^lncBADR-/-) exhibited markedly ameliorated experimental autoimmune encephalomyelitis (EAE) symptoms. Mechanistic investigations revealed that lncBADR inhibits BCAAs degradation by binding to the enzymes Mccc1 and Pcca, leading to the accumulation of BCAAs within T-cells. This, in turn, activates the mTOR-Stat1 signaling pathway, promoting IFN-γ secretion and exacerbating EAE pathology. In contrast, knockout of lncBADR restored BCAAs degradation, significantly reducing IFN-γ secretion in T cells and suppressing their pathogenic functions. Further studies demonstrated that high-BCAAs feeding partially reversed the protective effects of lncBADR knockout, indicating that lncBADR plays a crucial role in autoimmune inflammation by regulating BCAAs metabolism. This study offers new insights into targeting lncBADR or modulating BCAAs metabolism as potential therapeutic strategies for autoimmune diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"213"},"PeriodicalIF":10.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176145","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":"Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity in a sexually dimorphic manner.","authors":"Jiahui Liu, Ali Zaidi, Christian J Pike","doi":"10.1186/s12974-025-03534-z","DOIUrl":"10.1186/s12974-025-03534-z","url":null,"abstract":"<p><p>Obesity is associated with numerous adverse neural effects, including reduced neurogenesis, cognitive impairment, and increased risks for developing Alzheimer's disease (AD) and vascular dementia. Obesity is also characterized by chronic, low-grade inflammation that is implicated in mediating negative consequences body-wide. Toll-like receptor 4 (TLR4) signaling from peripheral macrophages is implicated as an essential regulator of the systemic inflammatory effects of obesity. In the brain, obesity drives chronic neuroinflammation that involves microglial activation, however the contributions of microglia-derived TLR4 signaling to the consequences of obesity are poorly understood. To investigate this issue, we first generated mice that carry an inducible, microglia/macrophage-specific deletion of TLR4 that yields long-term TLR4 knockout only in brain indicating microglial specificity. Next, we analyzed the effects of microglia/macrophage TLR4 deletion on systemic and neural effects of a 16-week of exposure to control versus obesogenic high-fat diets. In male mice, TLR4 deletion generally yielded limited effects on diet-induced systemic metabolic dysfunction but significantly reduced neuroinflammation and impairments in neurogenesis and cognitive performance. In female mice maintained on obesogenic diet, TLR4 deletion partially protected against weight gain, adiposity, and metabolic impairments. Compared to males, females showed milder diet-induced neural consequences, against which TLR4 deletion was protective. Collectively, these findings demonstrate a central role of microglia/macrophage TLR4 signaling in mediating the neural effects of obesogenic diet and highlight sexual dimorphic responses to both diet and TLR4.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"214"},"PeriodicalIF":10.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176118","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":"Macrophage expression of P2X7 controls autoimmune uveitis.","authors":"Paul-Alexandre Déchelle-Marquet, Yueshen Che, Camille Roux, Frédéric Blond, Kaitryn E Ronning, Sébastien Augustin, Pauline Lagouge-Roussey, Caroline Nous, Sara Touhami, Bahram Bodaghi, Jean Kanellopoulos, Sahil Adriouch, Xavier Guillonneau, Florian Sennlaub, Cécile Delarasse","doi":"10.1186/s12974-025-03529-w","DOIUrl":"10.1186/s12974-025-03529-w","url":null,"abstract":"<p><p>The release of danger-associated molecular patterns (DAMPs) such as ATP from stressed or damaged cells is a key initiator of sterile inflammation. In autoimmune diseases, extracellular ATP acts as a potent pro-inflammatory signal by activating the purinergic receptor P2X7, which is expressed on both mononuclear phagocytes (MPs) and T cells-key drivers of pathological processes. While it is well established that P2X7 mediates ATP-dependent immune activation, its cell-specific contributions to innate versus adaptive immunity in autoimmune conditions remain unclear, especially in autoimmune uveitis. Here we used the experimental autoimmune uveoretinitis (EAU) mouse model to delineate the cellular mechanisms underlying P2X7's role in autoimmune responses. Using a combination of multiple cell-specific conditional models and transcriptomic approaches, we showed a pivotal role forP2X7 expressed by MPs in orchestrating T-cell mediated autoimmune responses. P2X7 deficiency in MPs decreased disease severity. Additionally, cell-specific transcriptomic analyses, including single-cell analyses, revealed that P2X7 exerted distinct modulatory effects across monocyte-derived macrophages (MdM) versus microglia. In MdM, lack of P2X7 was associated with reduced expression of genes related to the inflammasome, phagocytosis pathways, and components of the complement system, leading to a marked decrease in pathogenic Th17 cell frequency in the retina. In microglia, P2X7 deficiency instead particularly impacted an IFN-responsive microglial subset that is normally characteristic of EAU. By specifically deleting P2X7 in microglia, we demonstrate its role in driving pathogenic processes in this cell population. These findings suggest that inhibition of P2X7 could be a promising therapeutic strategy in autoimmune neuroinflammatory disorders.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"212"},"PeriodicalIF":10.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149537","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":"Inhibition of Ephrin receptor signaling in the paraventricular nucleus attenuates psoriasis-like dermatitis via synaptic plasticity and immune homeostasis modulation.","authors":"Qingyu Ren, Zhanpeng Gao, Weikai Han, Yaqi Tang, Mengdong Shi, Yanan Yue, Xijia Xin, Chenyu Zhang, E Liu, Bo Dong, Qingwei Yue, Jinhao Sun","doi":"10.1186/s12974-025-03539-8","DOIUrl":"10.1186/s12974-025-03539-8","url":null,"abstract":"<p><p>Psoriasis pathophysiology involves dysregulated neuroimmune crosstalk, yet the central mechanisms involved remain incompletely understood. Here, we show that the hypothalamic paraventricular nucleus (PVN) orchestrates cutaneous inflammation via a transsynaptic brain-skin circuit. Using neural tracing and chemogenetic approaches, we revealed functional connectivity between the PVN and both sympathetic neurons and psoriatic skin. Reactivation of imiquimod (IMQ)-induced PVN-transgenic targeted recombination in active population (TRAP) neurons (which form a specific \"inflammatory memory\") is essential for psoriasis progression and can drive chronic inflammation. Single-nucleus RNA sequencing (snRNA-seq) identified ephrin receptor A7 (Epha7) as a critical mediator of synaptic plasticity in PVN inflammatory engram neurons. The inhibition of Ephrin receptor and ligand binding in the PVN normalized dendritic spine remodelling, suppressed sympathetic nerve hyperactivity, and restored the balance of Th17/Treg cells in psoriatic-like mice. Mechanistically, blockade of the Ephrin receptor attenuated sympathetic norepinephrine overflow, thereby mitigating Th17-driven inflammation. This study identifies a PVN-sympathetic-skin axis in which the inhibition of Epha7 in the PVN restores skin immune homeostasis. Furthermore, this study elucidates the central neural mechanisms of skin inflammation and promotes the transition of psoriasis treatment from single-target approaches to a synergistic neuroimmune strategy involving \"brain-skin\" interactions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"211"},"PeriodicalIF":10.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137809","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":"Knockout of P2Y12 receptor facilitates neuronal envelopment by reactive microglia and accelerates prion disease.","authors":"Natallia Makarava, Tarek Safadi, Olga Bocharova, Olga Mychko, Narayan P Pandit, Kara Molesworth, Ukpong B Eyo, Ilia V Baskakov","doi":"10.1186/s12974-025-03542-z","DOIUrl":"10.1186/s12974-025-03542-z","url":null,"abstract":"<p><strong>Background: </strong>Microglia continuously monitor neuronal health through somatic purinergic junctions, where microglial processes establish dynamic contacts with neuronal cell bodies. The P2Y12 receptor is a key component of these junctions, essential for intercellular communication between ramified microglia and neurons under homeostatic conditions. However, during chronic neurodegeneration, such as that seen in prion diseases, microglia transition from process-based surveillance to extensive body-to-body interactions, enveloping neuronal somata. Despite its widespread use as a homeostatic marker, the functional role of P2Y12 in chronic neurodegenerative contexts remains largely unexplored.</p><p><strong>Methods: </strong>We investigated how genetic deletion of P2Y12 affects microglial morphology and microglia-neuron interactions in both healthy and prion-infected adult mice. In parallel, we assessed the impact of P2Y12 loss on prion disease progression and associated neuropathology.</p><p><strong>Results: </strong>In healthy adult mice, deletion of P2Y12 significantly disrupted canonical process-to-soma contacts, while paradoxically promoting increased microglia-neuron body-to-body interactions. This finding uncovers a previously unrecognized, P2Y12-independent mode of microglial engagement with neurons. Strikingly, in prion-infected mice, P2Y12 loss significantly increased the prevalence of neuronal envelopment by reactive microglia, and accelerated disease progression. Notably, this acceleration occurred without affecting prion accumulation or hippocampal neuronal loss, implicating altered microglia-neuron interactions - specifically excessive envelopment - as a key driver of disease exacerbation.</p><p><strong>Conclusions: </strong>This study redefines P2Y12 not as a passive marker of homeostasis but as an active regulator of neuroimmune dynamics. We demonstrate that P2Y12 is essential for maintaining balanced microglia-neuron communication under physiological conditions and for restraining maladaptive microglial behavior during chronic neurodegeneration associated with prion disease. These findings uncover a novel mechanism by which microglia contribute to disease progression and position P2Y12 as a potential therapeutic target for modulating microglial responses in neurodegenerative disorders.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"210"},"PeriodicalIF":10.1,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12400595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957797","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":"Circulatory extracellular vesicles transport complement C1q for promoting neuronal amyloid-β production in Alzheimer's disease.","authors":"Yang Yu, Wenjun Xiao, Zhixin Ma, Xiaomei Yi, Tianyu Zhong, Zhigang Li","doi":"10.1186/s12974-025-03528-x","DOIUrl":"https://doi.org/10.1186/s12974-025-03528-x","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"209"},"PeriodicalIF":10.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957826","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":"P2X7-CaMKII drives 5-LOX nuclear translocation to impair microglial function after subarachnoid hemorrhage.","authors":"Peng-Fei Ding, Jia-Tong Zhang, Xiao-Long Zhu, Yue Cui, Chun-Lei Chen, Xun-Zhi Liu, Jun-Da Shen, Le-Xuan Zou, Yue Lu, Zong Zhuang, Chun-Hua Hang, Wei Li","doi":"10.1186/s12974-025-03530-3","DOIUrl":"https://doi.org/10.1186/s12974-025-03530-3","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"208"},"PeriodicalIF":10.1,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957831","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":"Disrupted betaine metabolism drives Th17 cell differentiation, mediating methamphetamine-induced depressive behaviors in male mice.","authors":"Rongji Hui, Jiabao Xu, Hongchen Ma, Tao Feng, Congcong Hou, Xintao Wang, Mingyang Jin, Feng Yu, Yan Shi, Bing Xie, Ludi Zhang, Bin Cong, Chunling Ma, Di Wen","doi":"10.1186/s12974-025-03532-1","DOIUrl":"https://doi.org/10.1186/s12974-025-03532-1","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"207"},"PeriodicalIF":10.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957846","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":"TLR9/NF-κB-mediated dendritic cell activation by neutrophil extracellular traps drives pathogenesis in experimental cerebral malaria.","authors":"Shijie Yao, Yan Zhao, Chao Yao, Qing Li, Mengna Sun, Qinghui Wang, Li Zheng, Yaming Cao","doi":"10.1186/s12974-025-03531-2","DOIUrl":"https://doi.org/10.1186/s12974-025-03531-2","url":null,"abstract":"<p><p>Cerebral malaria (CM) is the most severe complication of Plasmodium falciparum infection, and accounts for the majority of malaria-associated mortality. Reducing the overwhelming inflammatory responses in the early stage of infection is a key point to prevent death due to CM. In this study, we found that neutrophil mobilization occurred rapidly in response to Plasmodium berghei ANKA (PbA) infection in a murine CM model. Depletion of neutrophils protected the infected mice from neuropathology, with low infiltration and activation of CD8⁺ T cells in the brain, and attenuated activation of dendritic cell (DC) and parasite-specific T cell responses in the spleen. Flow cytometry analysis showed that following PbA infection the expression of TLR4, TLR7, and TLR9 were increased in splenic DC, while only TLR9 expression was reduced after the depletion of neutrophils. To validate the TLR9-dependent activation between neutrophils and DC, we used neutrophil extracellular traps (NETs) to stimulate bone marrow-derived DCs (BMDC) from WT and Tlr9^-/- mice. The results showed that the DNA component of NETs activates DCs through the TLR9/NF-κB signaling pathway, leading to upregulated expression of costimulatory molecules and the production of proinflammatory cytokines, which was abolished by DNase I. BMDC stimulated by NETs promoted CD8⁺ T cell activation with TLR9 dependence. Inhibiting NETs with Sivelestat effectively impeded the onset and progression of CM in the PbA infected mice. Collectively, our results indicated that neutrophil cell death (NETosis) induced TLR9-dependent DC activation and pathogenic CD8⁺ T cell responses, revealing that the NETs-TLR9/NF-κB-DC-CD8⁺ T cell axis may provide novel insights into the immunopathogenic mechanisms of CM.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"206"},"PeriodicalIF":10.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957819","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":"Single-cell transcriptomic landscape of sciatic nerve after transection injury.","authors":"Yiben Ouyang, Mingqian Yu, Tieyuan Zhang, Haofeng Cheng, Liang Zuo, Haolin Liu, Yanjun Guan, Ao Liu, Jiajie Chen, Ruichao He, Sice Wang, Tianqi Su, Yixiao Tan, Yuhui Cu, Xiaochun Zhang, Xiaoyang Fu, Junli Wang, Jinjuan Zhao, Jiang Peng, Yu Wang","doi":"10.1186/s12974-025-03514-3","DOIUrl":"https://doi.org/10.1186/s12974-025-03514-3","url":null,"abstract":"<p><p>Peripheral nerve injuries, particularly those affecting the sciatic nerve, often result in incomplete functional recovery due to the limited regenerative capacity of adult peripheral nerves. To elucidate the cellular and molecular mechanisms underlying nerve regeneration, we performed single-cell RNA sequencing (scRNA-seq) on rat sciatic nerve tissues at seven time points (Days 0, 1, 3, 5, 7, 10, and 14) following transection injury. Through unsupervised clustering, we identified four major cellular compartments-neurofibroblasts (NFs), glial cells (Glis), immune cells, and vascular cells-and delineated their dynamic trajectories during regeneration. Early responses were dominated by macrophage (Mac) and granulocyte infiltration (Day 1), followed by proliferative expansion of proliferating mesenchymal fibroblasts (NF5) and repair Schwann cells (Gli0) by Days 3-5. Vascular remodeling commenced from Day 7, while Glis progressively transitioned to mature myelinating states (Gli2/Gli5) by Day 14. Pseudotime analysis revealed subtype-specific reprogramming in both Macs and Glis, and cell-cell communication analysis uncovered key ligand-receptor interactions-particularly collagen and PTN signaling between Macs, NFs, and Glis. Bulk transcriptomic validation confirmed sustained and spatially distinct activation of the TGF-[Formula: see text] signaling pathway across cell types and anatomical locations. Comparative analysis with a sciatic nerve crush injury model revealed a stronger early immune response and delayed Gli recovery in transection injury, indicating a narrowed therapeutic window. Together, this work provides a time-resolved single-cell atlas of peripheral nerve regeneration, defines key regulatory circuits within the immune-NF-Gli axis, and identifies phase-specific therapeutic targets-such as early Mac heterogeneity, NF4-mediated matrix remodeling, and Schwann cell remyelination-for enhancing functional recovery following severe nerve injury.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"205"},"PeriodicalIF":10.1,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957808","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}