Journal of Neuroinflammation最新文献

{"title":"Nanozymes in neuropathic pain: strategies bridging oxidative stress, mitochondrial repair, and neuroimmune modulation for targeted therapy.","authors":"Muhammad Mohsin, Fizzah Shams, Hong Li, Amir Alam, Chaoyun Xia, Lulu Fan, Ying Cao, Wei Jiang, Abdul Nasir, Suliman Khan, Qian Bai","doi":"10.1186/s12974-025-03456-w","DOIUrl":"10.1186/s12974-025-03456-w","url":null,"abstract":"<p><p>Neuropathic pain is one of the most debilitating neurological conditions, significantly challenging to manage due to the complex interplay of oxidative stress, neuroinflammation, and mitochondrial dysfunction in its pathogenesis. Nanozyme (nanomaterials with enzyme-like activity) technology offers a promising strategy to tackle these multifaceted mechanisms. These nanozymes can scavenge reactive oxygen species (ROS), modulate inflammatory pathways, and reverse mitochondrial dysfunction, providing notable neuroprotection and pain relief for affected individuals. Additionally, nanozymes exhibit targeted delivery to the injury sites by using mechanisms such as lysosome-mediated endocytosis (e.g., SOD&Fe3O4@ZIF-8 nanozymes) and mannose receptor-mediated cellular uptake (e.g., mSPIONs nanozymes). Given the limitations of current treatment options, we underscore the advantages of nanozymes, including their multifunctional capabilities and potential to enhance therapeutic outcomes in pain management. This review focuses on the underlying mechanisms of neuropathic pain, particularly emphasizing the role of oxidative stress and its impact on disease progression. We examine the applications of nanozymes for treating neuropathic pain, highlighting their potential to scavenge ROS, relieve mitochondrial dysfunction, modulate neuroinflammatory pathways, and repair blood-spinal cord barrier integrity. Furthermore, this paper provides an overview of the current landscape of nanozyme research in neuropathic pain and future directions for their clinical translation in pain management, emphasizing their potential role in improving therapeutic outcomes.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"156"},"PeriodicalIF":9.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285033","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":"The dynamics of brain T cell populations during the course of rasmussen encephalitis: from expansion to exhaustion.","authors":"Katharina M Mair, Victoria Guggenberger, Laia Verdú de Juan, Ulrike Köck, Hans Lassmann, Roland S Liblau, Christian G Bien, Jan Bauer","doi":"10.1186/s12974-025-03477-5","DOIUrl":"10.1186/s12974-025-03477-5","url":null,"abstract":"<p><p>Rasmussen Encephalitis (RE) is a chronic, unilateral epileptic disorder mostly found in children. Neuropathologically, it is characterized by T lymphocyte infiltration targeting neurons and leading to microglia activation, astrogliosis, and cortical degeneration. Within a patient's brain, distinct pathological stages are found that offer a unique opportunity to study T cell dynamics in situ. Using quantitative multiplex fluorescence imaging, we analyzed CD103⁺ and CD69⁺ Tissue-resident memory T cells (T_RM) across different disease stages. This analysis revealed that T_RM were more abundant in the parenchyma than in the perivascular space, suggesting that their differentiation occurs locally after antigen encounter. Further, part of the T_RM expressed Granzyme-B (GrB) and frequently were attached to neurons, suggesting that they are actively involved in neuronal destruction. While T_RM showed a stage-dependent increase in older lesions, the proportions of these cells did not correlate with disease duration, indicating that their accumulation may be more dependent on the local environment in the lesion than on the length of the disease. In addition, we found that T cells using the γδ T cell receptor comprised up to 66%. Like CD8⁺ T cells, the γδ T cells could develop a T_RM phenotype and, while expressing GrB⁺ granules, they were seen attached to neurons, suggesting that they are involved in neuronal destruction. Finally, analysis of exhaustion- and T_RM-associated immune checkpoint control markers PD-1 and LAG-3 revealed a significant stage-dependent increase in PD-1 expression in the oldest lesions. In contrast, LAG-3 expression did not show any stage-specific pattern, pointing towards a distinct regulatory mechanism. The study demonstrates a dynamic and one-way T cell response throughout the course of RE at a given spot in the CNS: from the establishment of T cell residence after entry into the CNS, the killing of neurons, and eventually T cell exhaustion. It further suggests an important role of γδ T-cells in the propagation of disease and lesions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"155"},"PeriodicalIF":9.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285034","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":"OTUD1 exacerbates sepsis-associated encephalopathy by promoting HK2 mitochondrial release to drive microglia pyroptosis.","authors":"Guoqing Jing, Hailong Gong, Han Wang, Jing Zuo, Die Wu, Huifan Liu, Xing Wang, Min Yuan, Yun Xia, Tongtong Du, Wanhong Liu, Xiaojing Wu, Xuemin Song","doi":"10.1186/s12974-025-03480-w","DOIUrl":"10.1186/s12974-025-03480-w","url":null,"abstract":"<p><strong>Background: </strong>Sepsis-associated encephalopathy (SAE), a life-threatening neurological complication of systemic infection, contributes substantially to sepsis-related mortality. Accumulating evidence demonstrates that microglia-driven neuroinflammation emerges as a central pathogenic mechanism underlying SAE. Here, we identify ovarian tumor deubiquitinase 1 (OTUD1) as a critical mediator of SAE pathogenesis. We demonstrate that OTUD1 promotes hexokinase 2 (HK2) dissociation from mitochondria via selective K63-linked deubiquitination, triggering microglia pyroptosis and neuroinflammation. Our findings address a key knowledge gap by elucidating the OTUD1-HK2 axis as a novel regulatory pathway in SAE, offering potential therapeutic targets to mitigate cognitive deficits in sepsis.</p><p><strong>Methods: </strong>Single-cell RNA sequencing was used to identify SAE-specific microglia subpopulations and analyze the expression of deubiquitinases within these subpopulations. OTUD1 knockout mice were generated to investigate the role of OTUD1 in SAE. Both wild-type and OTUD1 knockout mice were subjected to cecal ligation and puncture to induce SAE. In vitro, primary microglia and BV2 cells were treated with LPS and nigericin to simulate inflammatory conditions. Cognitive function of the mice was assessed through behavioral tests. Neuronal and synaptic damage were evaluated using HE and Nissl staining, as well as transmission electron microscopy. ELISA and qPCR were used to detect neuroinflammation. Western blot and immunofluorescence were employed to analyze protein expression. Molecular docking, 3D confocal microscopy, and co-immunoprecipitation were conducted to detect the interaction between OTUD1 and HK2. Finally, the correlation between OTUD1 and SAE was evaluated by analyzing clinical samples.</p><p><strong>Results: </strong>Through single-cell RNA seq and subpopulation analysis, we identified an SAE-associated microglia (SAM) subpopulation with high expression of pyroptosis-related genes. Deubiquitinase expression analysis showed significantly elevated OTUD1 expression in SAM. OTUD1 deficiency attenuated neural damage and cognitive dysfunction in SAE mice in vivo. Further experiments revealed that OTUD1 regulates pyroptosis in microglia, affecting the progression of SAE. Mechanistically, OTUD1 directly binds to the C-terminal domain of HK2 through its Ala-rich domain and selectively cleaves K63-linked polyubiquitin chains on HK2 to promote the dissociation of HK2 from mitochondria, thereby activating the NLRP3 inflammasome and pyroptosis.</p><p><strong>Conclusions: </strong>In SAE, OTUD1 deubiquitinates HK2, promoting its dissociation from mitochondria, which triggers microglia pyroptosis, leading to neuronal damage and cognitive impairment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"154"},"PeriodicalIF":9.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12153095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275083","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":"Comprehensive analysis of immunoglobulin expression in the mouse brain from embryonic to adult stages.","authors":"Keiko Morimoto, Hitomi Sano, Michiko Takahashi, Rikuo Takahashi, Kazunori Nakajima","doi":"10.1186/s12974-025-03457-9","DOIUrl":"10.1186/s12974-025-03457-9","url":null,"abstract":"<p><p>Immunoglobulin (Ig) is a critical molecule in the body's defense against foreign substances such as bacteria and viruses. While traditionally considered B cell specific, studies have reported that Ig is also expressed by non-B cells. However, it is not known to what extent Ig is expressed in the brain and which type of variable regions are expressed. In this study, we elucidated the expression profile of Igs from embryonic to adult stages using single-cell RNA sequencing data and Ig repertoire analysis. Our results revealed that microglia express Ighm transcripts from embryonic to adult stages. These transcripts contain the upstream region of the Ighj region. In addition, Ighm is expressed in the layer 6 corticothalamic neurons, some of which co-express Ighg2c in the adult brain. In particular, we were able to generate a comprehensive profile of Ig variable region expression from embryonic to adult stages. Furthermore, the response of Ighm expression in microglia to lipopolysaccharide is markedly different from that in B cells, suggesting a novel, brain-specific role for the Ig gene, distinct from its classical function in the immune system.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"153"},"PeriodicalIF":9.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258296","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":"NEK2 regulates B cell function and the severity of experimental autoimmune encephalomyelitis.","authors":"Si-Ting Wu, Tian-Xiang Zhang, Zhirui Liu, Xueting An, Xiaoshan Du, Shu Yang, Ti Wu, Guanju Di, Jingshi Song, Bin Feng, Chunyang Wang, Chao Zhang","doi":"10.1186/s12974-025-03472-w","DOIUrl":"10.1186/s12974-025-03472-w","url":null,"abstract":"<p><p>Never in mitosis gene A (NIMA)-related kinase 2 (NEK2), a member of the serine-threonine kinase family, is critically involved in the regulation of the cell cycle. Upregulation of NEK2 is associated with aberrant B cell proliferation, a phenomenon potentially driven by NEK2-mediated disruption of the PKM1/PKM2 equilibrium. The overexpression of NEK2 in the B cell lineage may facilitate the maturation processes of B cells. Nonetheless, the precise role of NEK2 in modulating B cell-mediated immunity in autoimmune disorders remains to be fully elucidated. In this study, we demonstrate that NEK2 was significantly upregulated in multiple sclerosis (MS) patients. Pharmacological inhibition of NEK2 resulted in a marked reduction in the expression of co-stimulatory molecules CD80 and CD86 on B cells, concomitant with a suppression of their proliferation and differentiation into antibody-secreting cells (ASCs) and class-switched memory B cells (SWM). Administration of the NEK2 inhibitor INH1 in a murine model of experimental autoimmune encephalomyelitis (EAE) led to notable improvements in neurological function, amelioration of demyelination, and a decrease in the infiltration of inflammatory cells in the central nervous system (CNS) compared to vehicle-treated EAE mice. Mass cytometry analysis revealed that NEK2 inhibition downregulated the expression of co-stimulatory molecules and diminished the proportion of Th1 cells in the CD4 + T cell population. In vitro studies further substantiated that NEK2 blockade attenuated CD4 + T cell proliferation and differentiation into Th1 cells by disrupting B-T cell interactions. Collectively, these findings underscore an immunomodulatory function for NEK2 and highlight its potential as a therapeutic target in the treatment of multiple sclerosis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"152"},"PeriodicalIF":9.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248364","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":"Circulating T cell atlas in Moyamoya disease: insights into immunopathogenesis of cerebrovascular disorders.","authors":"Chenglong Liu, Junsheng Li, Siqi Mou, Yuheng Pang, Liujia Chan, Qiheng He, Wei Liu, Zhikang Zhao, Bojian Zhang, Zhiyao Zheng, Wei Sun, Xiangjun Shi, Qian Zhang, Rong Wang, Yan Zhang, Wenjing Wang, Dong Zhang, Peicong Ge","doi":"10.1186/s12974-025-03479-3","DOIUrl":"10.1186/s12974-025-03479-3","url":null,"abstract":"<p><strong>Background: </strong>Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive stenosis or occlusion of the intracranial arteries, accompanied by the formation of fragile collateral vessels, ultimately leading to ischemic or hemorrhagic strokes. Immune dysregulation, particularly involving T cell abnormalities and mitochondrial dysfunction, plays a critical role in the pathogenesis of MMD; however, their precise relationship remains unclear.</p><p><strong>Methods: </strong>Peripheral blood mononuclear cells (PBMCs) from patients with MMD and healthy controls were analyzed using mass cytometry (CyTOF) and transcriptomic profiling. Additionally, clinical characteristics and neuroimaging data were collected to perform integrated correlation analyses with immune profiling data.</p><p><strong>Results: </strong>Patients with MMD exhibited aberrant T cell activation and altered subset distribution, accompanied by mitochondrial dysfunction and impaired oxidative phosphorylation capacity. Increased oxidative stress and endoplasmic reticulum stress were observed in T cells, along with disease-specific downregulation of immune checkpoint molecules, including PD-1 and ICOS.</p><p><strong>Conclusions: </strong>This study highlights the critical involvement of immune activation and mitochondrial dysfunction in the pathophysiology of MMD, providing novel insights into disease mechanisms and identifying immunometabolic pathways as potential targets for therapeutic intervention.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"151"},"PeriodicalIF":9.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234370","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-dependent change in Th17 and cytokine response in multiple sclerosis.","authors":"Wen Zhu, Shankar Revu, Chenyi Chen, Megan Dahl, Archana Ramkumar, Conor Kelly, Mandy J McGeachy, Zongqi Xia","doi":"10.1186/s12974-025-03474-8","DOIUrl":"10.1186/s12974-025-03474-8","url":null,"abstract":"<p><strong>Background: </strong>Multiple sclerosis (MS) is a chronic autoimmune disease damaging the central nervous system. Diminished inflammatory disease activity (DA) as people with MS (pwMS) age motivated randomized clinical trials assessing disease-modifying therapy (DMT) discontinuation in older pwMS given the concern for risks outweighing benefits. This study aims to examine whether peripheral production of Myelin Basic Protein (MBP)-driven cytokine responses mediate the aging-associated decline in MS inflammatory DA.</p><p><strong>Methods: </strong>We included the clinical data of 669 adult pwMS between 2017 and 2022 who enrolled in a clinic-based prospective cohort. From a subset of 80 participants, we isolated fresh peripheral blood mononuclear cells (PBMCs) and cultured with 50 µg/ml of MBP (or heat-killed Candida) for 24 h. We assayed cell culture supernatants for interleukin 17 (IL-17) and interferon gamma (IFN-γ) using Enzyme-Linked Immunosorbent Assay and a subset of the supernatant samples using a commercial human cytokine/chemokine array. We examined the associations between age and annualized relapse rate (ARR) as well as between age and MBP-stimulated cytokine production (by cultured PBMC) using covariate-adjusted linear regressions. We performed mediation analyses to determine the extent to which MBP-driven cytokine response drives the association between age and ARR.</p><p><strong>Results: </strong>Among 669 pwMS (mean age 51.7 ± 12.7 years, 80.7% women, 89.4% non-Hispanic White), ARR declined with age (β=-0.003, p < 0.001). Among the subgroup of 80 pwMS whose cultured PBMCs underwent ex vivo MBP stimulation, IL-17 production declined with age in women (β=-0.27, p = 0.04) but not men (β=-0.1, p = 0.73). MBP-driven IL-17 response partially mediated the association between older age and lower ARR (24.6% in women, 15.3% in men). In exploratory analyses, older pwMS (≥ 50 years) had marginally lower (IL-4, MCP-2, MCP-3, PDGF-AA, PDGF-AB/BB) and higher (Fractalkine, MDC) concentrations of several cytokines than younger pwMS (< 50 years), while certain cytokines (MCP-2, MDC) mediated whereas others negated the effect of age on ARR.</p><p><strong>Conclusion: </strong>Diminished peripheral IL-17 response as a potential biological mechanism underlying the aging-dependent decline in MS inflammatory DA warrants further investigation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"150"},"PeriodicalIF":9.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234369","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":"From gut inflammation to psychiatric comorbidity: mechanisms and therapies for anxiety and depression in inflammatory bowel disease.","authors":"Kangcheng Luo, Mengting Zhang, Qianwen Tu, Jian Li, Youheng Wang, Songlin Wan, Daojiang Li, Qun Qian, Lu Xia","doi":"10.1186/s12974-025-03476-6","DOIUrl":"10.1186/s12974-025-03476-6","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"149"},"PeriodicalIF":9.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216151","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":"Inflammation-induced lysosomal dysfunction in human iPSC-derived microglia is exacerbated by APOE 4/4 genotype.","authors":"Marianna Hellén, Isabelle Weert, Stephan A Müller, Noora Räsänen, Pinja Kettunen, Šárka Lehtonen, Michael Peitz, Klaus Fließbach, Mari Takalo, Marja Koskuvi, Stefan F Lichtenthaler, Ville Leinonen, Alfredo Ramirez, Olli Kärkkäinen, Mikko Hiltunen, Jari Koistinaho, Taisia Rõlova","doi":"10.1186/s12974-025-03470-y","DOIUrl":"10.1186/s12974-025-03470-y","url":null,"abstract":"<p><strong>Background: </strong>The ε4 isoform of apolipoprotein E (ApoE) is the most significant genetic risk factor for Alzheimer's disease. Glial cells are the main source of ApoE in the brain, and in microglia, the ε4 isoform of ApoE has been shown to impair mitochondrial metabolism and the uptake of lipids and Aβ42. However, whether the ε4 isoform alters autophagy or lysosomal activity in microglia in basal and inflammatory conditions is unknown.</p><p><strong>Methods: </strong>Altogether, microglia-like cells (iMGs) from eight APOE3/3 and six APOE4/4 human induced pluripotent stem cell (iPSC) lines were used in this study. The responses of iMGs to Aβ42, LPS and IFNγ were studied by metabolomics, proteomics, and functional assays.</p><p><strong>Results: </strong>Here, we demonstrate that iMGs with the APOE4/4 genotype exhibit reduced basal pinocytosis levels compared to APOE3/3 iMGs. Inflammatory stimulation with a combination of LPS and IFNγ or Aβ42 induced PI3K/AKT/mTORC signaling pathway, increased pinocytosis, and blocked autophagic flux, leading to the accumulation of sequestosome 1 (p62) in both APOE4/4 and APOE3/3 iMGs. Exposure to Aβ42 furthermore caused lysosomal membrane permeabilization, which was significantly stronger in APOE4/4 iMGs and positively correlated with the secretion of the proinflammatory chemokine IL-8. Metabolomics analysis indicated a dysregulation in amino acid metabolism, primarily L-glutamine, in APOE4/4 iMGs.</p><p><strong>Conclusions: </strong>Overall, our results suggest that inflammation-induced metabolic reprogramming places lysosomes under substantial stress. Lysosomal stress is more detrimental in APOE4/4 microglia, which exhibit endo-lysosomal defects.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"147"},"PeriodicalIF":9.3,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208781","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":"Brd4 expression in CD4 T cells and in microglia promotes neuroinflammation in experimental autoimmune encephalomyelitis.","authors":"Anup Dey, Matthew Butcher, Anne Gegonne, Ryoji Yagi, Keita Saeki, Eunju Lee, Dinah S Singer, Jinfang Zhu, Keiko Ozato","doi":"10.1186/s12974-025-03449-9","DOIUrl":"10.1186/s12974-025-03449-9","url":null,"abstract":"<p><p>Microglia are resident innate immune cells in the central nervous system (CNS) that provides anti-microbial protection but also promote neuroinflammation. BRD4 is a chromatin reader that binds to acetylated histones and directs transcription of numerous genes. However, it is unknown whether and how BRD4 regulates microglia function. We addressed the role of microglia and BRD4 in a neuroinflammatory disease, experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. It was reported earlier that in EAE, upon initial T cell activation in the peripheral lymphoid organs, CD4⁺ T cells migrate to CNS and are reactivated by resident or migratory antigen presenting cells resulting in full manifestation of EAE (Rossi and Constantin, Front Immunol 7:506, 2016), (Plastini et al., Front Cell Neurosci 14:269, 2020). Using conditional deletion of Brd4 in CD4 T cells, we reveal that BRD4 regulates T helper cell differentiation and promotes T cell migration to CNS resulting in EAE. It remained unclear whether resident microglia are capable of reactivating migrating T cells to the CNS and if BRD4 plays a role in the process. To determine the role of microglial BRD4 in EAE, we constructed conditional knockout mice lacking Brd4 (Brd4cKO) in microglia. RNA-seq analysis showed that Brd4 deletion led to the downregulation of many microglia genes in both naive and EAE conditions. Consequently, Brd4cKO mice had markedly reduced EAE pathology, namely reduced paralysis, absence of axonal demyelination and inhibited expression of inflammatory cytokines. In vehicle treated mice (vehicle) abundant number of T cells were found to be near microglia that may lead to T cell- microglia interaction and T cell reactivation. In contrast, the number of T cells detected in the CNS of Brd4cKO mice was much fewer. This may lead to reduced T cell- microglia interaction, failure of T cells to get reactivated and hence failed to achieve full manifestation of EAE. These results demonstrate that microglia are critically involved in EAE disease progression for which BRD4 is essential. In summary, BRD4 directs transcription of genes defining microglia function. By so doing BRD4 promotes demyelination and neuroinflammation to exacerbate EAE.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"148"},"PeriodicalIF":9.3,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208780","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}