Journal of Neuroinflammation最新文献

{"title":"T cell-mediated SIV dissemination into the CNS: a single-cell transcriptomic analysis.","authors":"Xiaoke Xu, Meng Niu, Benjamin G Lamberty, Katy Emanuel, L Daniel Estrella, Howard S Fox","doi":"10.1186/s12974-025-03543-y","DOIUrl":"https://doi.org/10.1186/s12974-025-03543-y","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"226"},"PeriodicalIF":10.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251501","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":"A neuroimmune cerebral assembloid model to study the pathophysiology of familial Alzheimer's disease.","authors":"Andrea Becerra-Calixto, Anik Banerjee, Huihui Fan, Chunfeng Tan, Eunyoung Lee, Louise D McCullough, Juneyoung Lee","doi":"10.1186/s12974-025-03544-x","DOIUrl":"https://doi.org/10.1186/s12974-025-03544-x","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the leading cause of dementia globally. The accumulation of amyloid and tau proteins, neuronal cell death and neuroinflammation are seen with AD progression, resulting in memory and cognitive impairment. Microglia are crucial for AD progression as they engage with neural cells and protein aggregates to regulate amyloid pathology and neuroinflammation. Recent studies indicate that microglia contribute to the propagation of amyloid beta (Aβ) via their immunomodulatory functions including Aβ phagocytosis and inflammatory cytokine production. Three-dimensional cell culture techniques provide the opportunity to study pathophysiological changes in AD in human-derived samples that are difficult to recapitulate in animal models (e.g., transgenic mice). However, these models often lack immune cells such as microglia, which play a critical role in AD pathophysiology. In this study, we developed a neuroimmune assembloid model by integrating cerebral organoids (COs) with induced microglia-like cells (iMGs) derived from human induced pluripotent stem cells from familial AD patient with PSEN2 mutation. After 120 days in culture, we found that iMGs were successfully integrated within the COs. Interestingly, our assembloids displayed histological, functional and transcriptional features of the pro-inflammatory environment seen in AD, including amyloid plaque-like and neurofibrillary tangle-like structures, reduced microglial phagocytic capability, and enhanced neuroinflammatory and apoptotic gene expression. In conclusion, our neuroimmune assembloid model effectively replicates the inflammatory phenotype and amyloid pathology seen in AD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"227"},"PeriodicalIF":10.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251593","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":"Early antiviral treatment following gammaherpesvirus-68 infection of the central nervous system prevents subsequent multiple sclerosis-like disease.","authors":"Alexander Muselman, Sameera Kongara, Nathan Hsu, Asha Aggarwal, Joanna Yu, Jayakumar Rajadas, Edgar G Engleman","doi":"10.1186/s12974-025-03547-8","DOIUrl":"https://doi.org/10.1186/s12974-025-03547-8","url":null,"abstract":"<p><strong>Background: </strong>Growing evidence indicates that Epstein-Barr virus (EBV), a gammaherpesvirus, plays a central role in the pathogenesis of multiple sclerosis (MS). The presence of EBV-infected cells in the central nervous system (CNS) of MS patients, but not in neurologically healthy individuals, suggests that viral persistence in the CNS may drive MS. However, why there is such a long interval between initial infection and the development of disease is unknown.</p><p><strong>Methods: </strong>To model the effects of EBV infection on the brain, we intracerebrally infected mice with murine gammaherpesvirus-68 (MHV68), a virus genetically related to EBV that causes transient pathology strikingly similar to that seen in humans after acute EBV infection. One month following MHV68 infection, we administered myelin oligodendrocyte glycoprotein (MOG) peptide to evaluate the effects of prior MHV68 infection on the response to an additional inflammatory stimulus of the CNS. Virus persistence, microglial activation and immune cell infiltration were evaluated over time using flow cytometry.</p><p><strong>Results: </strong>Intracerebral MHV68 infection induced mild brain demyelination and ataxia, a common symptom of MS, that both quickly resolved. However, administration of MOG peptide one month later led to more severe brain demyelination and more sustained ataxia, suggesting that prior MHV68 infection sensitized the mice to a newly introduced immune stimulus. Further investigation revealed that following CNS infection, MHV68 persisted in microglia, where it induced a primed phenotype marked by elevated MHC-II expression and heightened immune reactivity for at least six months. Primed microglia displayed increases in the labile iron pool, and iron chelation reduced microglial priming. Early antiviral treatment during MHV68 infection completely prevented subsequent MOG-induced demyelinating disease.</p><p><strong>Conclusions: </strong>These findings support a two-step mechanism by which CNS infection with a gammaherpesvirus closely related to EBV sensitizes the host to a second unrelated immune stimulus that triggers MS-like disease manifestations. Chronic priming of microglia resulting from the initial infection contributes to this process, and prevention of such priming with early antiviral treatment also prevents neuropathology following the second stimulus. EBV infection may similarly sensitize humans to a second stimulus and, if so, treatment of acute EBV infection may avert subsequent MS development.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"228"},"PeriodicalIF":10.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251542","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":"NLRP3 inflammasome and hearing loss: from mechanisms to therapies.","authors":"Silvia Murillo-Cuesta, Elena Seoane, Blanca Cervantes, Jose Manuel Zubeldia, Isabel Varela-Nieto","doi":"10.1186/s12974-025-03561-w","DOIUrl":"10.1186/s12974-025-03561-w","url":null,"abstract":"<p><p>The NLRP3 inflammasome, a key component of the innate immune system, has emerged as a central mediator of inflammation-driven sensorineural hearing loss (SNHL). This review synthesizes current evidence on its involvement across a wide spectrum of auditory pathologies, including genetic syndromes such as CAPS and autosomal dominant deafness (DFNA) 34, as well as noise-induced, age-related, drug-induced, and viral hearing loss. Dysregulated activation of NLRP3 in the cochlea leads to the release of proinflammatory cytokines (IL-1B and IL-18) and pyroptotic cell death, contributing to irreversible cochlear damage. Experimental studies have demonstrated that pharmacological inhibition of NLRP3 via agents such as MCC950, oridonin and tranylcypromine can preserve auditory function. Gain-of-function mutations in the NLRP3 gene are frequently associated with both syndromic and nonsyndromic hearing loss, and animal models expressing these mutations replicate cochlear inflammation and hearing deficits, validating their pathogenic role. Clinically, IL-1B signaling blockers such as anakinra and canakinumab have shown efficacy in CAPS patients, stabilizing or improving hearing outcomes. Emerging selective NLRP3 inhibitors, including dapansutrilo and MCC950, are progressing through early-phase clinical trials. Additionally, natural compounds such as piceatannol and oridonin have demonstrated otoprotective effects in preclinical models of noise- and drug-induced hearing loss. Collectively, these findings position the NLRP3 inflammasome as a promising therapeutic target for SNHL. Future translational research should focus on validating NLRP3-targeting compounds in human trials, identifying biomarkers for early diagnosis, and exploring combination therapies that integrate anti-inflammatory, antioxidant, and regenerative strategies. Targeting NLRP3 may ultimately redefine treatment paradigms for preventing or halting progressive hearing loss.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"225"},"PeriodicalIF":10.1,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228440","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":"Cytokine expression profile in the human brain of older adults.","authors":"Juliana Beker Godoy, Ricardo A Vialle, Loren Dos Santos, Roberto T Raittz, Yanling Wang, Vilas Menon, Philip L De Jager, Julie A Schneider, Shinya Tasaki, David A Bennett, Dieval Guizelini, Katia de Paiva Lopes","doi":"10.1186/s12974-025-03552-x","DOIUrl":"10.1186/s12974-025-03552-x","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a complex neurodegenerative condition linked to chronic neuroinflammation. This study investigates the cytokine gene expression profile in cortical tissue samples from elderly individuals with and without AD to identify potential biomarkers and enhance our understanding of disease pathogenesis. Utilizing high-depth RNA sequencing data, we identified a set of cytokines whose expression significantly associated with different aspects of the AD phenotype, including measures of neurofibrillary tangles, amyloid-β deposition, and a person-specific rate of cognitive decline. Single-nucleus transcriptomics data facilitated the identification of specific cell types, such as microglia and astrocytes, that significantly contribute to the inflammatory response in AD. Additionally, we observed a correlation between the expression of certain cytokines and genetic risk for the disease. Our findings indicate that cytokine-mediated neuroinflammation may play an important role in neurodegeneration and that modulating the immune response may offer a promising strategy for developing new therapies.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"224"},"PeriodicalIF":10.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12495855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225676","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":"Neuro-immune regulation of sepsis-associated delirium via the PBN-CeA-spleen axis.","authors":"Menglin Dong, Yu Zou, Zhiwen Ye, Wangyuan Zou, Lina Zhang, Yuhang Ai, Qianyi Peng","doi":"10.1186/s12974-025-03527-y","DOIUrl":"10.1186/s12974-025-03527-y","url":null,"abstract":"<p><strong>Background: </strong>Sepsis associated delirium (SAD) is the most prevalent manifestation of acute brain dysfunction in sepsis, yet its central regulatory mechanisms remain incompletely understood. As researchers have progressively explored the brain-spleen axis and neuroimmunity, this study aimed to investigate the role of the parabrachial nucleus (PBN)-central amygdala (CeA)-spleen axis in the pathogenesis of SAD.</p><p><strong>Methods: </strong>In a mouse model of SAD induced by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg), we identified activation patterns in both the PBN and CeA using immunofluorescence analysis. We subsequently investigated direct anatomical connections between these regions through bidirectional neural tracing, followed by functional interrogation using fiber photometry and electrophysiological recordings. Finally, we evaluated the effect of targeted inhibition of the PBN-CeA pathway on delirium in septic mice through behavioral assays. Additionally, enzyme-linked immunosorbent assay (ELISA) and flow cytometry were employed for immunological profiling.</p><p><strong>Results: </strong>We observed a significant increase in c-Fos expression in both the PBN and CeA, and confirmed a direct anatomical connection between these regions. Fiber photometry and electrophysiological recordings revealed that LPS stimulation activated CeA neurons and splenic sympathetic nerves. In addition, targeted inhibition of the PBN-CeA pathway mitigated CeA calcium dynamics and reduced spontaneous splanchnic nerve discharge. Behavioral assays showed that splenic denervation and inhibition of the PBN-CeA pathway attenuated delirium-like behaviors in septic mice. ELISA and flow cytometry demonstrated that these interventions reversed splenic proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, IL-6, and IL-10, interferon-gamma [IFN-γ]) and norepinephrine (NE) while restoring immune cell composition and enhancing natural killer (NK) cell function.</p><p><strong>Conclusion: </strong>The PBN-CeA-splenic axis plays a critical neuroimmune conduit linking central neural circuits to peripheral immune modulation, offering new mechanistic insight into the neural regulation of systemic inflammation and the pathogenesis of SAD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"222"},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212996","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":"Microglial glycolytic reprogramming in alzheimer's disease: association with impaired phagocytic function and altered vascular proximity.","authors":"Ning Lu, Zhongman Jin, Nian Liu, Caiyun Zhu, Hui Wei, Qi Xu","doi":"10.1186/s12974-025-03546-9","DOIUrl":"10.1186/s12974-025-03546-9","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is characterized by chronic neuroinflammation alongside amyloid-beta plaque and phosphorylated tau (p-Tau) tangle accumulation. Microglia, as resident immune cells, undergo glycolytic reprogramming that may exacerbate inflammation and impede toxic protein clearance. Specifically, the glycolytic enzyme pyruvate kinase M2 (PKM2) drives proinflammatory microglial phenotypes linked to neurodegeneration. This study investigates how PKM2-mediated microglial glycolytic reprogramming and inflammatory responses alongside Aβ/p-Tau clearance in human AD brains.</p><p><strong>Methods and results: </strong>Hippocampal-entorhinal cortex (HP-EC) tissues from 8 AD patients and 8 matched controls underwent multiplex immunohistochemistry and high-resolution spatial analysis. PKM2⁺Iba1⁺ microglia density significantly increased in AD versus controls (p < 0.001), predominantly displaying a disease-associated microglial (HAM-like) phenotype (ABCA7⁺) with concurrent lipid-droplet accumulation (PLIN3⁺; LDAM phenotype). Spatially, glycolytic PKM2⁺Iba1⁺ microglia accumulated near Aβ plaques, p-Tau tangles, and cerebral vasculature. Notably, their distribution around plaques/tau showed anomalous increasing density with distance (p < 0.001), suggesting impaired chemotaxis. Perivascular localization lacked clear chemotactic gradients. Functionally, overall phagocytic activity (CD68⁺) decreased significantly in AD (p = 0.001), primarily attributed to PKM2- subsets, whereas PKM2⁺Iba1⁺ microglia exhibited pronounced phagocytic exhaustion (PLIN2⁺; p < 0.001), consistent around both Aβ and p-Tau lesions (all p < 0.001).</p><p><strong>Conclusion: </strong>Our study establishes that microglial glycolytic reprogramming via PKM2 promotes a proinflammatory HAM-like phenotype, phagocytic exhaustion, and peri-pathological accumulation with aggregates and cerebral vessels. Targeting glycolytic pathways represents a viable therapeutic strategy for alleviating microglial dysfunction and neuroinflammation in AD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"223"},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212914","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":"Cerebrospinal fluid neuronal pentraxin levels are associated with tau pathology via microglia-astrocyte signaling in alzheimer's disease.","authors":"Zihao Zhang, Xin Chen, Zehu Sheng, Na Jiang, Wen-Quan Zou","doi":"10.1186/s12974-025-03545-w","DOIUrl":"10.1186/s12974-025-03545-w","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have reported that Neuronal Pentraxin 2 (NPTX2), a synapse-associated protein, can significantly predict the progression of cognitive decline. However, the role of the NPTX protein family in the pathological progression of Alzheimer's Disease (AD) in humans remains unclear.</p><p><strong>Methods: </strong>This study included 263 participants from the Alzheimer's Disease Neuroimaging Initiative, including cognitively normal, mild cognitive impairment, and AD individuals, with a mean age of 73.99 ± 7.43 years. Cerebrospinal fluid (CSF) NPTX proteins and Glial Fibrillary Acidic Protein (GFAP) were quantified by Mass spectrometry, Soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) by a Meso Scale Discovery-based multiplex immunoassay, and amyloid-beta 42 (Aβ42), phosphorylated tau (P-tau), and total tau (T-tau) by Roche Elecsys immunoassays. We systematically evaluated the associations between NPTX proteins and baseline CSF AD biomarkers, as well as their relationships with longitudinal biomarker changes. Mediation models were applied to explore whether GFAP and sTREM2 mediate the associations between NPTX proteins and T-tau pathology. Additionally, subgroup analyses based on A/T/(N) classification were conducted to assess stage-specific effects, and sensitivity analyses were performed using 18 F-fluorodeoxyglucose Positron Emission Tomography in place of CSF AD biomarkers.</p><p><strong>Results: </strong>We found that CSF NPTX proteins were significantly associated with CSF sTREM2 (β_NPTX1 = 0.293, p < 0.001; β_NPTX2 = 0.387, p < 0.001; β_NPR = 0.382, p < 0.001), GFAP (β_NPTX1 = 0.274, p < 0.001; β_NPTX2 = 0.472, p < 0.001; β_NPR = 0.444, p < 0.001), and core AD biomarkers at baseline. The association between NPTX2 and T-tau levels was significant and independent of Aβ42 (β = 0.619, p < 0.001). Mediation analyses indicated that sTREM2 and GFAP, individually or sequentially, partially mediated the associations between NPTX and T-tau pathology, with stronger effects observed in the suspected non-AD pathology and Stage 2 groups. Pathway analysis suggested that NPTX may influence tau pathology and cognitive function through the sequential sTREM2→GFAP→T-tau or P-tau pathway.</p><p><strong>Conclusions: </strong>NPTX proteins are associated with tau-related pathology in AD, and CSF GFAP and sTREM2 may mediate these associations, with their roles potentially differing across stages of disease progression.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"221"},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212935","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":"Salt-sensitive hypertension promotes neuronal mitochondrial stress and neurodegenerative alterations via neuro-vascular metabolic reprogramming and local RAS signaling.","authors":"Hanxue Wu, Zihan Qiu, Junya Mu, Yi Wang, Jiawei Wang, Yue Han, Ruijie Yang, Shenglan Yuan, Miao Yuan, Rui Yang, Xingjuan Chen, Qi Sun, Fanni Li, Lei Xiao, Ming Zhang, Jiaxi Xu","doi":"10.1186/s12974-025-03533-0","DOIUrl":"10.1186/s12974-025-03533-0","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"220"},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212999","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":"Interferon-induced GTP-binding protein MX1 drives hyperexcitability in peripheral nerves: a novel mechanism in small fiber neuropathy.","authors":"Amanda C Y Chan, Hua Huang, Ameen Shah, Boxuan Zhang, Nicholas W J Foo, Ruolin Li, Nur Afiqah Binte Mohammad Rizal, Hiu Yi Wong, Hock Luen Teoh, Anselm Mak, Tuck Wah Soong, Vijay K Sharma, Herbert Schwarz","doi":"10.1186/s12974-025-03557-6","DOIUrl":"10.1186/s12974-025-03557-6","url":null,"abstract":"<p><p>Small fiber neuropathy (SFN) affects small-diameter sensory and autonomic nerve fibers, leading to chronic pain and autonomic dysfunction. While SFN can be associated with diabetes and autoimmune diseases, a significant proportion of cases are idiopathic. Although immune-mediated mechanisms are being recognized increasingly in SFN, their precise role remains unclear. This study investigates the presence of autoantibodies against interferon-induced GTP-binding protein MX (MX1) in SFN patients and explores their potential pathogenic role. A total of 59 patients with skin biopsy-confirmed SFN and 20 healthy controls were recruited. Serum samples were analyzed for the presence of anti-MX1 autoantibodies using enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was performed on rat sciatic nerves to assess the localization of patient IgG to unmyelinated nerve fibers, and immunocytochemistry and flow cytometry confirmed specific binding to MX1. Functional characterization of MX1 was conducted using whole-cell patch-clamp recordings in dorsal root ganglion (DRG) neurons overexpressing MX1. Additionally, protein interactions between MX1 and transient receptor potential cation channel subfamily C member 6 (TRPC6) were assessed using co-immunoprecipitation and surface biotinylation assays. Anti-MX1 autoantibody levels were significantly elevated in SFN patients compared to controls (p = 0.0278), particularly in the autoimmune SFN subgroup. Patient sera exhibited IgG binding to unmyelinated nerve fibers, with idiopathic and autoimmune SFN cases showing similar staining patterns, suggesting a similar immune-mediated mechanism. Immunocytochemistry showed binding to HEK293-MX1 cells and flow cytometry revealed higher MX1/WT fluorescence intensity ratios in patient sera, further confirming specific immune recognition of MX1. Patch-clamp recordings demonstrated that MX1 overexpression in DRG neurons led to significant membrane depolarization and increased action potential firing frequency (p < 0.0001), indicating heightened neuronal excitability. However, MX1 did not directly interact with TRPC6 or alter its function, suggesting an alternative pathway for its effects. The addition of anti-MX1 IgG did not further modify DRG electrophysiology, implying that the autoimmune component may contribute to SFN pathogenesis through indirect mechanisms. Our findings support the hypothesis that MX1 influences neuronal excitability and plays a role in SFN pathophysiology. Future studies should validate these findings in larger cohorts and explore potential therapeutic strategies targeting MX1-associated pathways in SFN.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"219"},"PeriodicalIF":10.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206778","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}