Ping-Chang Kuo , Zixuan Zhao , Barbara A. Scofield , Hallel C. Paraiso , I-Chen Ivorine Yu , Dennis A. Brown , Jui-Hung Jimmy Yen
{"title":"Benzoylacetonitrile as a novel anti-inflammatory compound on attenuating microglia and encephalitogenic T cell activation in experimental autoimmune encephalomyelitis","authors":"Ping-Chang Kuo , Zixuan Zhao , Barbara A. Scofield , Hallel C. Paraiso , I-Chen Ivorine Yu , Dennis A. Brown , Jui-Hung Jimmy Yen","doi":"10.1016/j.jneuroim.2025.578557","DOIUrl":"10.1016/j.jneuroim.2025.578557","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is an autoimmune disorder and characterized by immune-mediated neuroinflammation and demyelination triggered by the CNS resident immune cells, microglia (MG), and CNS infiltrating pathogenic T cells. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS, and MG activation and pathogenic Th1/Th17 cell infiltration is responsible for EAE development and progression. We previously demonstrated that benzoylacetonitriles exerted neuro-immunomodulatory activity and identified compound 7a (referred to henceforth as BTA) as promising analog. Here, we investigated whether BTA possessed effects on modulating inflammatory responses in EAE and assessed its effects on MG activation and pathogenic Th1/Th17 differentiation and CNS infiltration in EAE. Our results showed BTA ameliorated disease severity in the chronic C57BL/6 EAE model. Further studies demonstrated BTA suppressed MG activation, attenuated CNS Th1/Th17 infiltration, and inhibited peripheral Th1/Th17 differentiation in EAE. Using protein array, we confirmed BTA inhibited MG activation by suppressing inflammatory cytokines/chemokine production. Furthermore, BTA suppressed Th1/Th17 polarization <em>in vitro</em>, indicating a direct suppressive effect of BTA on Th1/Th17 differentiation. Finally, our results showed that BTA prevented disease relapse in the relapsing-remitting SJL EAE model. In conclusion, our study demonstrates BTA possessed protective and therapeutic effects by ameliorating disease severity in the chronic EAE and mitigating relapse in the relapsing-remitting EAE, respectively. Further analysis revealed BTA exerted effects on inhibiting MG activation and Th1/Th17 differentiation, demonstrated by <em>in vivo</em> and <em>in vitro</em> studies. Altogether, our results suggest the benzoylacetonitrile scaffold could be developed as a novel therapeutic agent for MS/EAE treatment.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"401 ","pages":"Article 578557"},"PeriodicalIF":2.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kaitlyn M. Marino , Daniel C. Shippy , Tyler K. Ulland
{"title":"Sugar utilization by microglia in Alzheimer's disease","authors":"Kaitlyn M. Marino , Daniel C. Shippy , Tyler K. Ulland","doi":"10.1016/j.jneuroim.2025.578552","DOIUrl":"10.1016/j.jneuroim.2025.578552","url":null,"abstract":"<div><div>Diabetes is a major risk factor for Alzheimer's disease (AD), yet the effect of specific carbohydrate sources in the diet on AD pathology remains unclear. The primary neuroimmune cell, microglia, undergo a metabolic shift during neuroinflammation associated with AD pathology. We utilized existing gene expression data and identified changes in sugar transporters (increased <em>Slc2a1</em> (glucose) and decreased <em>Slc2a5</em> (fructose) expression). To examine gene expression with respect to primary sugar source, N9 cells, a mouse microglia cell line, were cultured in glucose or fructose supplemented media and stimulated with lipopolysaccharide (LPS). RNA-sequencing analyses indicated significant changes between control and sugar supplemented media and several differentially expressed genes between glucose and fructose media. Concurrently, 5XFAD mice received equicaloric diets with specific carbohydrate sources: dextrose or fructose. Regardless of diet, sex, or genotype, all mice developed high blood sugar levels; confocal microscopy analyses indicated similar amyloid plaque burden and microglial response relative to the control diet, but there was a change in the microglial response between dextrose and fructose fed mice. Overall, these data indicate microglia preferentially express sugar transporters and sugar source may influence microglial reactivity in response to plaque pathology.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"401 ","pages":"Article 578552"},"PeriodicalIF":2.9,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CD47-blocking antibody interferes with neutrophil extracellular traps formation after spinal cord injury to reduce spinal cord edema","authors":"Yuhang Diao, Mingyu Hao, Minghao Xie, Xiaojun Hu, Rui Tan, Zhitan Wang, Hongtao Rong, Tao Zhu","doi":"10.1016/j.jneuroim.2025.578553","DOIUrl":"10.1016/j.jneuroim.2025.578553","url":null,"abstract":"<div><h3>Objective</h3><div>Our goal was to investigate the role of neutrophil extracellular traps (NETs) in the disruption of the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI) and to evaluate the therapeutic efficacy of CD47-blocking antibodies in mitigating the disruption.</div></div><div><h3>Methods</h3><div>We utilized Evans blue extravasation to evaluate BSCB permeability and immunofluorescence to evaluate the formation of NETs and the expression of ZO-1, CD31, S100A8/A9, CD68, GFAP, Iba-1, and NeuN. Spinal cord edema was quantified by comparing the dry and wet weights of tissue samples. We used enzyme-linked immunosorbent assay (ELISA) to evaluate inflammatory factors, including IL-1β, IL-6, and TNF-α. Changes in genes associated with NET formation were identified by mRNA sequencing. Activation of the TLR4-NF-κB-MMP2/MMP9 signaling pathway was examined via Western blot analysis. Limb function was evaluated using the Basso Mouse Scale (BMS) to assess motor function.</div></div><div><h3>Results</h3><div>We observed massive aggregation of neutrophils and the formation of neutrophil extracellular traps (NETs) after spinal cord injury. The use of CD47-blocking antibodies reduced NET formation, mitigated S100A8/A9 production, attenuated BSCB injury, decreased inflammatory cell infiltration, alleviated spinal cord edema, and minimized neuronal death at the site of injury. Furthermore, these antibodies suppressed activation of the TLR4-NF-κB-MMP2/MMP9 signaling pathway.</div></div><div><h3>Conclusion</h3><div>The use of CD47-blocking antibodies post-SCI resulted in reduced NET formation. By suppressing the TLR4-NF-κB-MMP2/MMP9 signaling pathway, these antibodies contributed to the preservation of blood-spinal cord barrier (BSCB) integrity, highlighting their potential as a therapeutic strategy for SCI.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"400 ","pages":"Article 578553"},"PeriodicalIF":2.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xingxing Zhang , Que Liu , Siyuan Li , Rong Wu , Ying Xiong , Yuhang Wang , Yun Gu , Zhixiu Song , Jiaxuan Gong , Shaoyun Zhao
{"title":"Traditional pediatric massage exerted an antidepressant effect and activated IGF-1/Nrf2 pathway in CUMS-exposed adolescent rats","authors":"Xingxing Zhang , Que Liu , Siyuan Li , Rong Wu , Ying Xiong , Yuhang Wang , Yun Gu , Zhixiu Song , Jiaxuan Gong , Shaoyun Zhao","doi":"10.1016/j.jneuroim.2025.578554","DOIUrl":"10.1016/j.jneuroim.2025.578554","url":null,"abstract":"<div><div>The activation of insulin-like growth factor-1 (IGF-1)/nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway contributes to enhance anti-inflammatory M2 microglia polarization and inhibit proinflammatory M1 microglia polarization, which is essential to resist neuroinflammation and thus resist depression. The prevalence of depression is high in adolescents, who are hypersensitive to chronic stress. Traditional pediatric massage (TPM) can effectively relieve depression. In this study, we investigated the action mechanism of TPM on preventing depression-like behaviors in adolescent rats exposed to chronic unpredictable mild stress (CUMS). In this investigation, we employed several behavioral tests and detections, including western blotting, immunofluorescence staining and RT-qPCR. The findings of this study demonstrated that TPM had an effectively antidepressant effect, maintained microglia polarization homeostasis and resisted neuroinflammation in the hippocampus in CUMS-exposed adolescent rats. With the treatment of picropodophyllin, the inhibitor of IGF-1 receptor, the antidepressant effect of TPM was blocked, along with inhibited IGF-1/Nrf2 pathway which were closely related with anti-inflammatory and anti-ferroptosis actions. The results suggest that TPM enhanced the resilience of adolescent rats to CUMS and exerted an antidepressant effect partially via activating IGF-1/Nrf2 pathway.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"400 ","pages":"Article 578554"},"PeriodicalIF":2.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Rheumatoid meningitis in the absence of active synovitis: A potential association of semaphorin 4A","authors":"Keishu Murakami , Yoshiaki Nakayama , Shigeru Iwata , Seiji Emori , Shoko Yorozu , Takao Fujii , Katsuichi Miyamoto","doi":"10.1016/j.jneuroim.2025.578548","DOIUrl":"10.1016/j.jneuroim.2025.578548","url":null,"abstract":"<div><div>Rheumatoid meningitis (RM) is a rare complication that can develop even in patients with inactive rheumatoid arthritis (RA). Currently, there are no reliable indicators that reflect the disease activity of RM, and its pathogenesis remains poorly understood. Herein, we presented three cases of RM without active synovitis and investigated the possible association between RM and semaphorin 4A (Sema4A). Two of the three patients with RM developed sudden onset of seizures, while one patient exhibited a slowly progressive gait disturbance and cognitive impairment. All the patients had inactive synovitis, positive anti-cyclic citrullinated peptide antibodies in the serum, high-intensity lesions on the cerebral surface on head magnetic resonance imaging, or a favorable response to glucocorticoids. Serum and cerebrospinal fluid (CSF) Sema4A levels in patients with RM were elevated during the acute phase compared to those in the remission phase. Serum Sema4A was significantly increased in patients with RM than in RA controls (23.8 ng/ml versus 7.48 ng/ml, <em>p</em> = 0.014), although there were no significant differences in RA disease activity between the two groups. Sema4A was expressed in a few infiltrating cells and stromal tissues of the RM leptomeninges. This is the first report to demonstrate that serum and CSF Sema4A levels correlate with the disease activity of RM sine active synovitis. The expression of Sema4A in the leptomeninges may be associated with RM pathogenesis.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"400 ","pages":"Article 578548"},"PeriodicalIF":2.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Min Zhang, Xiaomei Zhu, Lifei Yu, Zhixu Fang, Yi Wang, Linmei Zhang
{"title":"Pediatric anti-CaVα2δ autoimmune encephalitis: A case report and literature review","authors":"Min Zhang, Xiaomei Zhu, Lifei Yu, Zhixu Fang, Yi Wang, Linmei Zhang","doi":"10.1016/j.jneuroim.2025.578550","DOIUrl":"10.1016/j.jneuroim.2025.578550","url":null,"abstract":"<div><div>Anti-voltage-gated calcium channel alpha-2/delta subunit (anti-CaVα2δ) encephalitis is a rare autoimmune encephalitis (AE), with only two cases of anti-CaVα2δ AE have been reported in the literatureto date. The clinical characteristics and prognosis of this rare AE need to beexpanded.We present the case of a 9-year-oldgirl, who initially presented with fever and lymphadenitis, which progressed to headaches, drowsiness, frequent seizures, cognitive impairment, memory loss, and involuntary movements. Brain magnetic resonance imaging revealed lesions in the bilateral external capsule. Moreover, anti-CaVα2δ antibodies were detected (1,30) 3 and 5 weeks after symptom onset. Video electroencephalography revealed slow, severely diffuse, background activity with multifocal epileptiform discharges. Although the patient was administered a combined immunotherapy consisting of intravenous immunoglobulin, intravenous methylprednisolone, and rituximab, sheexhibited persistent neurological sequelae at the last follow-up (Modified Rankin Scale score of 4; Pediatric Quality of Life Inventory score of 75). Whileour case shares similar clinical characteristics with previously reported anti-CaVα2δ AE cases, our patientwas unresponsive to immunotherapy and experienced severe neurological sequelae during follow-up. This report broadens the clinical phenotype and prognosis associated with this rare condition, providing further information and clinical insights for the management of future cases.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"401 ","pages":"Article 578550"},"PeriodicalIF":2.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yujia Liu , Hanxiao Sun , Yingchen Xu , Binbin Xuan , Guofang Xia , Jifeng Tang , Jinpiao Lin , Ailian Du , Huiming Sheng
{"title":"Identification and characteristics of a novel CD8αα T cell subset in a refractory myasthenia gravis patient","authors":"Yujia Liu , Hanxiao Sun , Yingchen Xu , Binbin Xuan , Guofang Xia , Jifeng Tang , Jinpiao Lin , Ailian Du , Huiming Sheng","doi":"10.1016/j.jneuroim.2025.578551","DOIUrl":"10.1016/j.jneuroim.2025.578551","url":null,"abstract":"<div><div>Myasthenia gravis (MG) is an autoimmune disease that impairs neuromuscular transmission. Autoantibodies and cellular immunity mediate the immunopathology of MG, yet the mechanism of CD8<sup>+</sup> T cells in this process remains elucidated. In this study, we discovered a novel subset of CD8αα<sup>+</sup> T cells in the peripheral blood of an 18-year-old Chinese man diagnosed as MG, who has undergone thymectomy and persistent myasthenia crisis. Designated as CD161<sup>neg</sup> T cell, this subset was characterized by TCRαβ<sup>+</sup>CD8αα<sup>+</sup>PLZF<sup>+</sup>Vα7.2<sup>+</sup> but notably lacked CD161, distinct from mucosal-associated invariant T (MAIT) cells known for high CD161. The patient exhibited unusually high levels of CD161<sup>neg</sup> T cells compared to other MG patients, which fluctuated with infections but not MG severity. RNA sequencing revealed that CD161<sup>neg</sup> T cells lacked the genes characteristic of mature MAIT cells including <em>CCR6</em>, <em>CXCR6</em>, <em>ZBTB16</em>, and <em>IL18RAP</em>, but expressed cytotoxic T cell-related genes <em>GZMH</em> and <em>IFNG</em>. This study shed new light on the heterogeneity and complexity of CD8αα<sup>+</sup> T cells in MG patients with thymoma.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"400 ","pages":"Article 578551"},"PeriodicalIF":2.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Haitao Ren , Mange Liu , Min Qian, Yingmai Yang, Guan Hongzhi
{"title":"Cerebellar ataxia and depression associated with anti-RhoGTPase-activating protein 26 antibody: A case report","authors":"Haitao Ren , Mange Liu , Min Qian, Yingmai Yang, Guan Hongzhi","doi":"10.1016/j.jneuroim.2025.578547","DOIUrl":"10.1016/j.jneuroim.2025.578547","url":null,"abstract":"<div><div>Neuroimmune disorders associated with anti-RhoGTPase-activating protein 26 immunoglobulin G (IgG) autoantibodies (ARHGAP26; also termed anti-Ca) are infrequent and manifest a significant diversity in clinical presentations, including cerebellar ataxia, psychotic disorders, and cognitive impairments. This case report describes a middle-aged female who developed subacute cerebellar ataxia and depression. Detection of anti-ARHGAP26 IgG in both serum and cerebrospinal fluid (CSF) led to her diagnosis of primary autoimmune cerebellar ataxia, supported by her medical history of Sjögren's syndrome and the identification of CSF-specific oligoclonal bands. After undergoing sequential immunotherapy including corticosteroid, intravenous immunoglobulin, plasma exchange, mycophenolate mofetil and rituximab, her Scale for the Assessment and Rating of Ataxia score improved from 28.5 to 18, demonstrating partial recovery. This case highlights the necessity of considering an autoimmune etiology in patients presenting with subacute cerebellar ataxia and suggests that testing for ARHGAP26-IgG is warranted also when psychocognitive impairment is clinically evident. Early initiation of immunotherapy is important to enhance patient outcomes.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"400 ","pages":"Article 578547"},"PeriodicalIF":2.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tzu-Ying Chuang , Brenna A. LaBarre , Osman Corbali , Brian C. Healy , Shrishti Saxena , Talia B. Feldman , Eunnindy Sanon , Taylor J. Saraceno , Tanuja Chitnis
{"title":"Endocrine disrupting chemicals in early MS disease activity","authors":"Tzu-Ying Chuang , Brenna A. LaBarre , Osman Corbali , Brian C. Healy , Shrishti Saxena , Talia B. Feldman , Eunnindy Sanon , Taylor J. Saraceno , Tanuja Chitnis","doi":"10.1016/j.jneuroim.2025.578546","DOIUrl":"10.1016/j.jneuroim.2025.578546","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Epidemiological data shows that the prevalence of multiple sclerosis (MS) and the female-to-male sex ratio among MS patients are increasing over time. Endocrine disrupting chemicals (EDCs) are ubiquitous and increasingly recognized for effects on estrogen signaling. This study aimed to determine whether there was an association between EDC levels and disease severity in newly diagnosed, female MS patients.</div></div><div><h3>Methods</h3><div>This exploratory observational cohort study enrolled female patients, ages 18–60, via written informed consent from the Brigham MS Center. Enrollment criteria included diagnosis with MS within the past 5 years and completion of a questionnaire about potential EDC exposures. Exclusion criteria were intravenous steroids in the past 30 days. Collection processes and materials were designed to avoid EDC contamination. Urine samples were analyzed by NSF International (Ann Arbor, Michigan).</div><div>Primary outcome measures were MRI parameters and clinical disease activity, including multivariable analysis adjusting for MS treatment types. Spearman correlation test was used for analysis and between group comparisons were conducted with one-way ANOVA.</div><div>Results: 68 patients with MS were enrolled. In the phthalates, mEOHP was negatively correlated with T2 lesion volume over time (R value = −0.522, <em>p</em>-value = 0.002, Bonferroni adjusted <em>p</em> = 0.03). For the phenols, triclocarban was negatively associated with cheese consumption (R value = −0.402, <em>p</em> = 0.001, Bonferroni adjusted <em>p</em> = 0.012) There was no association between EDCs and disease activity or demographic factors, nor significant correlation with exposure to household plastics.</div></div><div><h3>Conclusion</h3><div>This exploratory study identified a negative correlation between triclocarban and cheese consumption. Longitudinally, phthalate metabolite mEOHP was negatively correlated with T2 lesion volume over time. Exposure to EDCs may affect the early disease course in MS, and expansion of research efforts is warranted.</div></div>","PeriodicalId":16671,"journal":{"name":"Journal of neuroimmunology","volume":"400 ","pages":"Article 578546"},"PeriodicalIF":2.9,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}