Journal of Neuroinflammation最新文献

{"title":"Editorial expression of concern: Dimethyl fumarate alleviates the nitroglycerin (NTG)-induced migraine in mice.","authors":"Giovanna Casili, Marika Lanza, Alessia Filippone, Michela Campolo, Irene Paterniti, Salvatore Cuzzocrea, Emanuela Esposito","doi":"10.1186/s12974-026-04087-5","DOIUrl":"10.1186/s12974-026-04087-5","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182546","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 influence of anti-CD20-directed B cell depletion across different agents on Epstein-Barr virus-specific humoral and cellular immunity in patients with multiple sclerosis.","authors":"Jakob Stögbauer, Saskia Bronder, Niklas Saenz Kämpfer, Celina Kron, Gabriel Gonzalez-Escamilla, Katharina Schwartz, Beatrice Tocariu-Krick, Eszter Nemeth, Wenlin Hao, Chiara Huber, Sven G Meuth, Olaf Stüve, Rebecca Urschel, Tina Schmidt, Sergiu Groppa, Martina Sester, Mathias Fousse","doi":"10.1186/s12974-026-04062-0","DOIUrl":"10.1186/s12974-026-04062-0","url":null,"abstract":"<p><strong>Background: </strong>Epidemiological evidence has established a central role of Epstein-Barr virus (EBV) in the pathogenesis of multiple sclerosis (MS). While EBV-specific T-cell responses may influence disease progression, the impact of anti-CD20 B-cell depletion therapy (BCDT) on EBV-specific cellular and humoral immunity remains insufficiently characterized, particularly in comparison with healthy controls (HC), untreated people with MS (pwMS), and pwMS on different BCDT agents.</p><p><strong>Main body: </strong>Methods In this cross-sectional study, pwMS receiving BCDT, untreated pwMS at initial diagnosis (MS-ID), and age- and sex-matched HC were enrolled. EBV-specific and polyclonal CD8⁺ and CD4⁺ T-cell responses were quantified and functionally characterized following stimulation with a EBV-derived peptide-mix predominately containing MHC class I binding peptides or Staphylococcus aureus enterotoxin B (SEB) using multiparametric flow cytometry. Anti-EBNA1- and anti-VCA-IgG levels were measured by ELISA.</p><p><strong>Results: </strong>A total of 183 participants were included: 54 pwMS receiving BCDT (mean age 47.0±15.6 years; 31 females), 107 controls (47.2±18.3 years, 54 females), and 22 MS-ID (33.4±11.1 years, 20 females). EBV-specific CD8⁺ and CD4⁺ T-cell levels were similar in controls and MS-ID. In contrast, BCD-treated pwMS showed significantly lower frequencies of EBV-specific CD8⁺ (p<0.0001) and CD4⁺ T cells (p=0.0004) than controls, and lower EBV-specific CD8⁺ T-cell levels than MS-ID (p=0.0023). In contrast, polyclonally stimulated CD8⁺ T-cell responses were largely comparable across groups, indicating preserved polyclonal T-cell function. EBV-specific CD8⁺ T cells in both patients and controls were predominantly polyfunctional, coexpressing IFNγ, IL-2, and TNF. Longer BCDT duration was associated with lower frequencies of EBV-specific CD8⁺ T cells (p=0.0003). Ofatumumab-treated patients exhibited higher EBV-specific CD8⁺ T-cell frequencies than ocrelizumab-treated patients (p<0.0001). Despite BCDT, anti-EBNA1- and anti-VCA-IgG levels were significantly higher in pwMS than in MS-ID or controls, and were unrelated to treatment duration, disease duration, disability, or BCDT agents.</p><p><strong>Conclusions: </strong>Unlike in treatment-naïve pwMS, BCDT is associated with selectively lower EBV-specific T-cell frequencies while EBV-specific and polyclonal T-cell functionality was largely preserved. In contrast, EBV-specific antibody levels were persistently higher despite treatment. Given the remarkably high clinical efficacy of BCDT in this cohort, the findings support a prominent role of EBV-specific cellular immunity in ongoing MS pathophysiology and suggest that reduced EBV-reactive T-cell responses may contribute to this potency. Differences between BCDT agents warrant further investigation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074663","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":"Estrogen deprivation exacerbates Alzheimer's disease pathology through neuronal CTSS signaling.","authors":"Renzhi Yang, Lin Shao, Fang Huang, Ying He, Meng Yuan, Qilong Wu, Sen Lin, Kai Guo, Hongsheng Zhang","doi":"10.1186/s12974-026-03970-5","DOIUrl":"10.1186/s12974-026-03970-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD) exhibits a pronounced sex bias, with women facing disproportionately higher risk and more severe pathology. Postmenopausal estrogen decline is implicated in this vulnerability, yet the molecular mechanisms linking estrogen loss to AD pathogenesis remain incompletely understood. Here, we demonstrate that ovariectomy (OVX) in female 5xFAD mice significantly exacerbates amyloid-β (Aβ) pathology, cognitive deficits, neuroinflammation, and reduces synaptic markers. Pharmacological blockade of estrogen receptor signaling recapitulated these effects, confirming their dependence on estrogen receptor pathways. Single-nucleus RNA sequencing (snRNA-seq) revealed widespread transcriptional reprogramming across brain cell types following estrogen deprivation, with prominent upregulation of the lysosomal protease cathepsin S (Ctss) and the AD risk gene ApoE. Remarkably, partial genetic reduction of CTSS prevented OVX-induced Aβ accumulation, glial activation, and synaptic decline in female 5xFAD mice, establishing CTSS as a critical downstream mediator of estrogen deficiency-driven pathology. Our findings provide mechanistic insight into sex-biased AD vulnerability and identify CTSS as a promising therapeutic target for mitigating AD risk in postmenopausal women.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13570535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955713","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 kallikrein-kinin system modulates CD4⁺ T cell function and contributes to T cell migration into the brain after stroke.","authors":"Nadine Gausmann, Steffen Haupeltshofer, Rebecca D Szepanowski, Sina Luppus, Egor Dzyubenko, Jasmin Bahr, Stine Mencl, Janine Gronewold, Dirk M Hermann, Michael Forsting, Cornelius Deuschl, Jan Buer, Astrid M Westendorf, Christoph Kleinschnitz, Ana I Casas, Wiebke Hansen","doi":"10.1186/s12974-026-04034-4","DOIUrl":"10.1186/s12974-026-04034-4","url":null,"abstract":"<p><p>Ischemic stroke elicits a sustained thromboinflammatory response that critically shapes secondary brain injury. The kallikrein-kinin system (KKS) has been identified as the interface of vascular injury and inflammatory processes; however, its role in adaptive immunity remains poorly defined. Here, we show that the KKS is associated with pathogenic CD4⁺ T cell activation and trafficking. In both ischemic stroke patients and mice subjected to transient middle cerebral artery occlusion (tMCAO), circulating CD4⁺ T cells exhibited a conserved, activated, and trafficking-competent phenotype characterized by upregulation of adhesion/migration markers, indicating a translationally preserved systemic adaptive immune response. Functionally, serum from stroke mice subacutely treated with a plasma kallikrein (PK)-neutralizing antibody (ɑPK) attenuated CD4⁺ T cell activation, proliferation, expression of adhesion/migration markers, and pro-inflammatory cytokine production in vitro. PK selectively enhanced CD4⁺ T cell adhesion and migration, while its downstream metabolite Des-Arg⁹-bradykinin (Des-Arg⁹-BK) induced a pronounced pro-inflammatory, pro-migratory phenotype and potentiated chemokine-driven transendothelial migration in vitro. Strikingly, delayed PK inhibition in vivo was associated with reduced T cell accumulation in the ischemic brain and increased circulating CD4⁺ T cell frequencies, suggesting impaired central nervous system (CNS) infiltration dynamics. Together, these findings support a role for KKS signaling in shaping neuroimmune interactions after ischemic stroke by enhancing endothelial adhesiveness and facilitating CD4⁺ T cell migration to the ischemic tissue. By linking thromboinflammation and adaptive immunity, the KKS emerges as a promising therapeutic target to selectively modulate neuroimmune interactions and potentially improve functional recovery after ischemic stroke.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148897504","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":"Editorial Expression of Concern: Biliverdin reductase-A attenuated GMH induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway.","authors":"Yiting Zhang, Yan Ding, Tai Lu, Yixin Zhang, Ningbo Xu, Devin W McBride, Jiping Tang, John H Zhang","doi":"10.1186/s12974-026-04005-9","DOIUrl":"10.1186/s12974-026-04005-9","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840462","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 locus coeruleus at the crossroads of inflammation and neurodegeneration in multiple sclerosis.","authors":"Intakhar Ahmad, Rebecca Alemani, Douglas L Feinstein","doi":"10.1186/s12974-026-03981-2","DOIUrl":"10.1186/s12974-026-03981-2","url":null,"abstract":"<p><strong>Background: </strong>Multiple sclerosis (MS) is increasingly recognized as a systems-level disorder encompassing grey matter injury, network disconnection, and neuropsychiatric symptoms alongside demyelination. Within this framework, the locus coeruleus (LC), the principal source of noradrenaline (NA) in the central nervous system, emerges as a plausible regulatory hub within a distributed monoaminergic network.</p><p><strong>Main body: </strong>LC-derived NA shapes microglial and astrocytic reactivity, oxidative stress, mitochondrial function, oligodendrocyte differentiation, and blood-brain barrier stability through adrenergic receptor signaling. Neuropathological studies show LC neuron loss, astrogliosis, and altered NA levels in MS and related animal models. Post-mortem findings suggest that neuromelanin-bound metals and redox-active trace elements selectively accumulate in LC neurons, potentially triggering mitochondrial dysfunction, barrier disruption, and chronic glial activation. In animal models, pharmacological or genetic reductions in NA worsen inflammation, demyelination, and axonal damage, while increasing NA improves disease outcomes and restores glial and cytokine profiles. Early clinical studies of β₂-adrenergic agonists and NA-modulating drugs suggest benefits across specific symptom domains, including relapse activity, fatigue, mood, bladder function, and selected cognitive measures, but remain limited by small cohorts and insufficient stratification of patients.</p><p><strong>Conclusions: </strong>Together, these findings support LC-NA dysfunction as a targetable aspect of MS pathobiology and justify biomarker-driven trials that combine noradrenergic interventions with molecular indicators of glial activity, myelin integrity, and stress-related signaling.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912543","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":"Riluzole shifts glial responses to protect synapses and memory in Aβ oligomer-treated rats.","authors":"Min-Kaung-Wint-Mon, Hiroyuki Kida, Ryoichi Kimura, Dai Mitsushima","doi":"10.1186/s12974-026-03972-3","DOIUrl":"10.1186/s12974-026-03972-3","url":null,"abstract":"<p><strong>Background: </strong>Soluble Aβ_1-42 (amyloid beta) oligomers are potent neurotoxins that disrupt synaptic function, alter glial responses, and lead to memory impairment in Alzheimer's disease (AD). Riluzole, a glutamate modulator approved for amyotrophic lateral sclerosis, reduces neuronal hyperexcitability, yet its in vivo effects on Aβ oligomer-induced cognitive dysfunction and glial alterations remain incompletely understood. Here, we investigated whether riluzole ameliorates Aβ_1-42 oligomer-induced memory impairment and associated hippocampal pathology.</p><p><strong>Methods: </strong>Aβ_1-42 oligomers were bilaterally microinjected into the dorsal CA1 region of freely moving male rats, followed by daily riluzole administration for 7 days. Then, the animals underwent a battery of behavioural tests before being sacrificed for immuno-histochemical studies. Glial engulfment of Aβ and synapse was visualized through multiplex immunohistochemistry combined with super-resolution microscopy and three-dimensional (3D) reconstruction.</p><p><strong>Results: </strong>Behavioral analyses revealed that riluzole significantly improved hippocampus-dependent memory, including contextual learning and spatial working memory, without affecting locomotor activity, anxiety-like behavior, or pain sensitivity. At the cellular level, riluzole reduced neuronal Aβ accumulation which was strongly associated with improved learning performance across individual animals. It enhanced robust Aβ internalization and lysosomal processing within astrocytes and microglia. Though Aβ-induced glial recruitment and activation persisted, riluzole enhanced morphological remodeling and shifted glial cells towards neuroprotective phenotype. Riluzole also attenuated Aβ-induced neuronal apoptosis, dendritic degeneration, and dendritic spine loss across the dorsal CA1 sublayers, and limited complement-mediated synaptic elimination by microglia.</p><p><strong>Conclusion: </strong>By enhancing glial Aβ clearance and preserving synaptic integrity, riluzole effectively counteracts Aβ-driven cognitive decline. Together, these findings highlight coordinated glial remodeling as a physiologically relevant mechanism at a therapeutically actionable stage of AD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149061857","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":"Retraction Note: Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models.","authors":"Michiyo Iba, Changyoun Kim, Michelle Sallin, Somin Kwon, Anjali Verma, Cassia Overk, Robert A Rissman, Ranjan Sen, Jyoti Misra Sen, Eliezer Masliah","doi":"10.1186/s12974-026-04011-x","DOIUrl":"10.1186/s12974-026-04011-x","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13499324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794531","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":"Correction: Adenosine A3 receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury.","authors":"Susan A Farr, Salvatore Cuzzocrea, Emanuela Esposito, Michela Campolo, Michael L Niehoff, Timothy M Doyle, Daniela Salvemini","doi":"10.1186/s12974-026-03998-7","DOIUrl":"https://doi.org/10.1186/s12974-026-03998-7","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13480252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794513","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":"NLRC5 restricts Japanese encephalitis virus replication and neuroinflammation by interacting with the viral NS3 protein in an IFN-γ-dependent manner.","authors":"Prasanjit Jena, Rohit Soni, Abhigya Chhetri, Vinay Sharma, Vengadesan Krishnan, Thomas A Kufer, Arup Banerjee","doi":"10.1186/s12974-026-04001-z","DOIUrl":"10.1186/s12974-026-04001-z","url":null,"abstract":"<p><strong>Background: </strong>NLRC5 is a known activator of MHC class I genes and a regulator of type I interferon activity. Although its expression increases in brains infected with Japanese encephalitis virus (JEV), its specific contribution to JEV pathogenesis and neuroinflammation remains unclear.</p><p><strong>Methods: </strong>We utilised in vitro cell cultures, in silico modelling, and in vivo mouse knockdown models of NLRC5 to investigate its impact on JEV replication, antiviral immune responses, central nervous system (CNS) inflammation, and overall disease progression.</p><p><strong>Results: </strong>JEV infection upregulated NLRC5 expression in the brain, microglia, and non-neuronal cells, but not in neuronal cells. However, NLRC5 expression could be induced in neuroblastoma cells via IFN-γ treatment. Experimental modulation demonstrated that the typical antiviral restriction of JEV replication by IFN-γ is lost in NLRC5-deficient cells. Evaluation of stable cell lines expressing different NLRC5 variants showed that cytoplasmic retention and NLRC5 leucine-rich repeats (LRRs) are essential for viral restriction. Mechanistically, in silico modelling, co-immunoprecipitation, and immunofluorescence confirmed that NLRC5 binds directly to the viral NS3 protein in an LRR-dependent manner. In mouse models, in vivo knockdown of NLRC5 in the brain significantly accelerated clinical disease progression, heightened mortality, and triggered uncontrolled viral replication, indicated by elevated viral titers and NS3/NS1 expression. This viral surge induced severe neuroinflammation, as evidenced by significantly elevated levels of ASC and cleaved caspase-3 in NLRC5-deficient brains.</p><p><strong>Conclusions: </strong>These findings demonstrate that NLRC5 functions as a cell-type-specific antiviral regulator during JEV infection. It suppresses viral replication by directly binding to and degrading the viral NS3 protein. Loss of NLRC5 impairs IFN-γ-mediated antiviral restriction, leading to enhanced viral replication, severe neuroinflammation, and accelerated disease progression in vivo.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13463953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720709","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}