Journal of Neuroinflammation最新文献

{"title":"The complement system in Alzheimer's disease: evaluating biomarker potential in a complex neuroimmune context.","authors":"Heli Soni, Greg T Sutherland, Markus J Hofer","doi":"10.1186/s12974-026-03927-8","DOIUrl":"10.1186/s12974-026-03927-8","url":null,"abstract":"<p><p>Neuroinflammatory processes are increasingly recognised as important modulators of Alzheimer's disease (AD) progression, driving interest in immune-related biomarkers beyond classical pathological measures. Among these, the complement system has attracted attention because of its interactions with amyloid-β (Aβ) and tau pathology, genetic associations with AD risk, and evidence of activation within affected brain regions. However, these biological observations do not directly translate into straightforward biomarker signals. Complement activity is highly dynamic, spans multiple activation and regulatory states, and may reflect both central and peripheral immune processes. This complexity limits interpretation when complement markers are assessed in isolation, as age, systemic inflammation, vascular comorbidity, and blood-brain barrier integrity can influence measured levels. Current evidence does not support complement-derived biomarkers as stand-alone diagnostic classifiers comparable to established amyloid, tau, and neurodegeneration (AT(N)) measures. Their independent or additive value within multimodal biomarker frameworks remains unclear, partly because of cohort heterogeneity, incomplete assay harmonisation, uncertain tissue-source attribution, and limited longitudinal validation. This review critically evaluates complement-derived measures as biologically informative markers of neuroimmune activity in AD, distinguishing biological plausibility from analytical and clinical utility. We argue that their most defensible current role is within multimodal biomarker frameworks, where they may provide context-specific information on inflammatory state rather than function as independent diagnostic, staging, or treatment-monitoring tools. Progress toward clinical application will require rigorous standardisation, mechanistic clarification, and validation across large, longitudinal, and diverse cohorts.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308552","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":"Gasdermin D-dependent neutrophil pyroptosis exacerbates Coxsackievirus A6-induced neuroinflammation through NET formation.","authors":"Quanman Hu, Dong Li, Yaqi Xie, Fang Wang, Tiantian Sun, Wangquan Ji, Peiyu Zhu, Jinzhao Long, Haiyan Yang, Shuaiyin Chen, Yuefei Jin, Guangcai Duan","doi":"10.1186/s12974-026-03916-x","DOIUrl":"10.1186/s12974-026-03916-x","url":null,"abstract":"<p><strong>Background: </strong>Coxsackievirus A6 (CVA6) is a nonenveloped, single-stranded RNA virus linked to neurological complications. Emerging evidence suggests neutrophil pyroptosis drives inflammation. However, the role of neutrophil pyroptosis in CVA6 pathogenesis remains unexplored.</p><p><strong>Methods: </strong>Ten-day-old wild-type (WT), Caspase-1 KO, and GSDMD KO mice were infected with a lethal dose of CVA6. For in vivo and in vitro studies, we used the caspase-1 inhibitor belnacasan, disulfiram, and anti-Ly6G antibody. We also generated neutrophil-specific PAD4-knockout mice (PAD4 Ne-KO) by deleting Padi4 under the S100A8 promoter. Post-infection, clinical scores, survival, and body weight were monitored. Brain tissues and bone marrow-derived neutrophils (BMDNs) were collected for analysis. Key methods included qPCR, Western blotting, histology/immunofluorescence, flow cytometry, and TEM to assess pyroptosis, inflammation, and immune cell infiltration. Findings were further validated using blood samples from HFMD patients.</p><p><strong>Results: </strong>In this study, we investigated how the Caspase-1/GSDMD pathway mediates neutrophil extracellular trap (NET) release and drives CVA6-induced neuroinflammation. CVA6 infection increased neutrophil numbers in mouse brain and peripheral blood, along with elevated MPO-DNA-a NET marker. In BMDNs, degranulation and NET formation occurred by 24 hpi, accompanied by Caspase-1/GSDMD activation. Caspase-1 knockout prolonged survival and reduced GSDMD-N expression in brain neutrophils; pharmacological Caspase-1 inhibition decreased mature IL-1β and IL-18 in brain tissue and suppressed CVA6 replication in BMDNs. Together, in vitro and in vivo data indicate that Caspase-1/GSDMD activation and NETosis critically contribute to CVA6-induced brain injury. This was confirmed by GSDMD knockout or disulfiram-mediated GSDMD inhibition, both of which markedly reduced NET release and neuropathology. Notably, global neutrophil depletion worsened infection-suggesting a protective role-whereas neutrophil-specific PAD4 knockout improved survival. Clinically, GSDMD expression showed a significant positive correlation with NETosis markers in patient samples from CVA6-infected individuals.</p><p><strong>Conclusion: </strong>These findings enhance understanding of enteroviral pathogenesis, identify GSDMD as a promising therapeutic target, and provide a novel framework for developing precision interventions that reduce excessive inflammation without impairing essential host defenses.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13339694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148302082","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 crosstalk in the tumor microenvironment: mechanisms and therapeutic implications for cancer immunotherapy.","authors":"Zezhi Fan, Na Wang, Bo Zhang, Kaiyuan Deng, Jiangjiang Fu, Li Ma, Junyi Li, Zhifang Xu, Yi Guo","doi":"10.1186/s12974-026-03933-w","DOIUrl":"10.1186/s12974-026-03933-w","url":null,"abstract":"<p><p>The nervous system is a critical regulator of the tumor microenvironment (TME), extending beyond structural innervation to influence tumor initiation, progression, and therapeutic response. Neural regulation operates through synapse-like interactions and paracrine, neurotransmitter-mediated, and electrochemical signaling, thereby shaping both malignant and stromal compartments. These signals modulate immune-cell phenotypes, promote T-cell exhaustion, and expand immunosuppressive populations, thereby contributing to immune evasion and resistance to immunotherapy. Emerging evidence highlights bidirectional crosstalk, whereby neural activity supports tumor growth, metastasis, metabolic reprogramming, and immune suppression, while tumor-derived signals reciprocally remodel neural activity. This dynamic crosstalk defines a neuro-immune-tumor regulatory network that represents an important layer of tumor biology. Despite recent advances, how neural, immune, and metabolic pathways are integrated within the TME remains incompletely understood. Cancer neuroscience has therefore emerged as an interdisciplinary field for elucidating these mechanisms and identifying therapeutic vulnerabilities. Targeting the neuro-immune axis through neuromodulation, neuroactive agents, and combination immunotherapy may improve immunotherapy efficacy and advance precision oncology.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295431","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":"Targeting the neuro-immune axis: immunological mechanisms and therapeutic strategies in male sexual dysfunction.","authors":"Zheng Hu, Jun Luo, Jianyun Lou, Juntao Deng, Zi Tao Gong, Jinming Chen","doi":"10.1186/s12974-026-03911-2","DOIUrl":"10.1186/s12974-026-03911-2","url":null,"abstract":"<p><p>Male sexual dysfunction (MSD) is a multifactorial condition in which traditional models focusing on vascular, endocrine, and psychogenic factors are insufficient. Emerging evidence highlights dysregulated crosstalk between the nervous and immune systems-the neuroimmune axis-as a potential unifying pathological substrate. This review synthesizes fragmented yet compelling evidence linking neural injury, chronic inflammation (both systemic and neurogenic), and immune dysregulation to the pathogenesis of MSD. We propose a novel integrative framework in which disruption of the neuro-immune axis serves as a convergent pathway for diverse etiologies, ranging from diabetic neuropathy to chronic pelvic pain. Central to this framework is the concept that immune-mediated processes exacerbate neural and vascular damage, creating a self-perpetuating cycle of dysfunction. Building on this mechanistic perspective, we explore the translational potential of neurosurgical and neuromodulatory strategies-such as sacral neuromodulation and vagus nerve stimulation-to restore neuroimmune homeostasis. Although direct clinical evidence in MSD remains limited, insights from related fields, including chronic pain and autoimmune disorders, provide a strong rationale for further investigation. This review aims to bridge mechanistic insights with therapeutic innovation, charting a course for future research into precision neuromodulation as a promising frontier for refractory MSD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295470","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":"Early-life lung injury and the developing brain: a lung-brain axis perspective on neurodevelopmental disorders.","authors":"Chengwei Li, Fei Wang, Xiaoyi Tang, Lezhen Wang, Chenhe Liu, Xiangning Chen, Wenyuan Lyu, Dongliang Li, Jianjun Li, Xiangyi Kong, Penghui Wei","doi":"10.1186/s12974-026-03912-1","DOIUrl":"10.1186/s12974-026-03912-1","url":null,"abstract":"<p><p>Emerging evidence indicates that early-life lung injuries-including bronchopulmonary dysplasia, childhood asthma, recurrent respiratory infections, and environmental tobacco smoke exposure-are significantly associated with an increased risk of neurodevelopmental disorders such as cognitive impairment, autism spectrum disorder, attention-deficit/hyperactivity disorder, and emotional or behavioral affections. The developing brain is particularly vulnerable during infancy and childhood, and pulmonary insults during this critical window may disrupt normal neurodevelopment through multiple interconnected mechanisms along the lung-brain axis. These mechanisms include the hypoxia-oxidative stress axis, which impairs oligodendrocyte maturation and myelination; pulmonary microvascular injury leading to neuronal energy metabolism dysregulation; systemic inflammation-mediated disruption of the blood-brain barrier; and a cascade from pulmonary inflammation to neuroinflammation, characterized by microglial activation, synaptic dysfunction, and impaired myelination. Together, these pathways converge to produce long-lasting neurodevelopmental consequences. Understanding the lung-brain axis provides a novel theoretical framework for explaining this comorbidity and highlights the need to integrate neurodevelopmental risk assessment and early intervention into the clinical management of early-life lung diseases. Future research should focus on longitudinal cohorts, identification of critical developmental windows, and targeted therapeutic strategies that address both pulmonary and neurological health.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283708","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":"Tau knockout mitigates long-term cognitive impairment following neonatal sepsis via mechanisms involving dendritic structural remodelling and adult hippocampal neurogenesis.","authors":"Hongchun Li, Bin Yu, Bingqiao Wang, Luqiang Sun, Chenhao Zhao, Linlin Hu, Mengqi Yuan, Haichuan Wang","doi":"10.1186/s12974-026-03917-w","DOIUrl":"10.1186/s12974-026-03917-w","url":null,"abstract":"<p><p>One of the leading causes of morbidity and mortality in newborns and preterm infants is neonatal sepsis, which is defined as a systemic inflammatory response caused by a suspected or confirmed infection that occurs during the first month of life. Adolescents who survive neonatal sepsis often experience severe long-term cognitive impairment and unfavourable neurological outcomes. The foetal brain expresses the Tau protein, a neuronal microtubule-associated protein that is essential for modulating neuronal development, and negative neurodevelopmental effects are linked to aberrant Tau expression. In this study, we investigated the possible role of Tau in the long-term memory and cognitive function deficits caused by neonatal sepsis. We discovered that Tau silencing could attenuate the memory impairment in adolescents caused by early-life inflammation. Furthermore, Tau silencing ameliorated this loss of long-term memory and cognitive function by promoting dendritic structural remodelling in granule neurons and adult hippocampal neurogenesis (AHN) in the hippocampus dentate gyrus (DG). Together, these results suggest that Tau is a possible molecular target for treating neonatal sepsis-induced brain damage and that Tau may influence deficits in long-term memory and cognitive function caused by neonatal sepsis by interfering with the dendritic structure of granule neurons and AHN during neuronal development.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148277675","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":"Human iPSC-derived neurons stimulated with IFNγ present HLA class I-restricted antigens to cytotoxic CD8⁺ T cells.","authors":"Benjamin Ds Clarkson, Susanna Pucci, Brittany L Overlee, Ramila Barun Shrestha, Kiran K Mangalaparthi, Remya Raja, Pei Shang, Marion Curtis, Akhilesh Pandey, Charles L Howe","doi":"10.1186/s12974-026-03915-y","DOIUrl":"10.1186/s12974-026-03915-y","url":null,"abstract":"<p><p>Multiple sclerosis lesions are dominated by clonally expanded CD8⁺ T cells within an IFNγ-rich inflammatory microenvironment and neurons may be targets of these effector cells. However, the peptide antigens that CD8⁺ T cells recognize on neurons are largely undefined. Neurons constitutively express low levels of HLA class I, and whether inflamed human neurons are competent to present a class I ligandome, what that ligandome contains, and whether presentation has functional consequences for autoreactive CD8⁺ T cells remain open questions. Here we combine human iPSC-derived neural aggregates (HNAs), HLA class I immunoprecipitation coupled to LC-MS/MS immunopeptidomics, and microfluidic co-culture assays to map IFNγ-induced HLA class I presentation by neurons and to test antigen-specific cytotoxicity. IFNγ stimulation induced HLA class I upregulation in HNAs and enabled recovery of a canonical 8-12-mer class I ligandome enriched for 9-mers. Neuron-restricted expression of a synapsin-driven polyepitope cassette yielded presentation of defined exogenous 9-mer peptides on donor HLA class I molecules and, in the presence of IFNγ, elicited activation of autologous antigen-specific CD8⁺ T cells and antigen-dependent neurite injury. Across four donors, comparative immunopeptidomics identified IFNγ-associated neural peptide repertoires that were distinct from those of matched fibroblasts and enriched for predicted HLA-B binding peptides. β2-microglobulin deletion ablated peptide recovery, and neuron-restricted reconstitution enabled identification of candidate neuron-derived peptides, including recurrent neurofilament light (NEFL)-derived peptides detected across donors. Together, these findings establish a human iPSC-derived platform for studying inflammatory neuronal HLA class I antigen presentation and antigen-dependent CD8⁺ T cell engagement.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264882","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 IRF7-induced lipophagy impairment aggravates lipid droplet overload and impedes neurological recovery after ischemic stroke.","authors":"Jing Yin, Yan Li, Yu-Lu Miao, Xue-Fang Song, Yao Cheng, Yu-Jie Zhai, Jia Ren, Cai-Hong Yang, Hui-Feng Zhang, Xiang-Nan Zhang, Li-Jun Yang, Yan-Ying Fan","doi":"10.1186/s12974-026-03902-3","DOIUrl":"10.1186/s12974-026-03902-3","url":null,"abstract":"<p><p>Lipid droplet (LD) accumulation in microglia results in a dysfunctional and proinflammatory state after ischemic stroke and worsens neurological outcomes; yet how this accumulation is regulated remains unclear. Interferon regulatory factor 7 (IRF7) is an immune regulatory factor whose role in lipid metabolism and autophagy has been increasingly studied in peripheral tissues. However, the role of IRF7 in microglial lipophagy (a selective autophagic process that targets LDs) and poststroke functional recovery remains unexplored. In this study, using a mouse photothrombotic ischemia (PTI) model, we observed that microglia in the peri-infarct region displayed persistent lipophagy impairment and LD accumulation for up to 21 days. Reanalysis of the single-cell RNA sequencing (scRNA-seq) dataset revealed that an Irf7^high microglial MG1 subcluster (disease-associated microglia) was significantly associated with autophagy and lipid metabolism poststroke. Furthermore, microglial Irf7 conditional knockout (Irf7 cKO) mice exhibited a significant rescue of lipophagy impairment and an alleviation of the ensuing LD accumulation in microglia, accompanied by enhanced synaptic plasticity and motor functional recovery during the subacute phase poststroke. Consistently, in the 15-month-old distal middle cerebral artery occlusion (dMCAO) model, Irf7 cKO mice also displayed similar improvements. Similar results were also observed in vitro. Mechanistically, Gnai2 was identified as a positively regulated transcriptional target of IRF7. In BV2 cells and primary microglia, Gnai2 knockdown mitigated lipopolysaccharide (LPS)-induced lipophagy impairment, thereby reducing LD accumulation. This treatment also increased the level of phosphatidylcholine (PC), a key lipid for stabilizing small LDs as well as promoting autophagosome formation and autophagic flux. Consistently, microglial Irf7 deletion or knockdown attenuated stroke- or LPS-induced PC reduction both in vivo and in vitro. Furthermore, exogenous supplementation with CDP-choline, an intermediate in PC synthesis, alleviated LD accumulation and lipophagy impairment, thereby improving motor function. Additionally, delayed administration of an inhibitor of stimulator of interferon genes (STING, an upstream target of IRF7) replicated the beneficial effects observed in Irf7 cKO mice, and its effects were not further enhanced by microglial Irf7 deletion. Taken together, these novel findings reveal that persistent impairment of microglial lipophagy is a key contributor to poststroke LD accumulation, and that IRF7 is involved in this process through direct transcriptional activation of Gnai2, which reduces the PC levels. Suppressing IRF7 with a STING inhibitor is a potential strategy for modulating microglial lipid metabolism and promoting functional recovery following stroke.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271920","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":"HMGB1-mediated endoplasmic reticulum stress in monocyte-derived dendritic cells regulates CD4+ T cell immune responses in myasthenia gravis.","authors":"Qing Zhang, Zhongya Gu, Yaxuan Li, Mengge Yang, Xue Ma, Xuanxuan Pan, Zhuajin Bi, Jing Lin, Mengcui Gui, Furong Wang, Min Zhang, Zhijun Li, Bitao Bu","doi":"10.1186/s12974-026-03908-x","DOIUrl":"10.1186/s12974-026-03908-x","url":null,"abstract":"<p><strong>Introduction: </strong>Myasthenia gravis (MG) is an autoimmune disorder characterized by immune dysregulation at the neuromuscular junction. Monocyte-derived dendritic cells (moDCs) are increasingly recognized as key drivers of MG pathogenesis; however, the mechanisms that govern their dysfunction remain incompletely understood.</p><p><strong>Methods: </strong>This study integrated human genetics, patient immunophenotyping, and therapeutic evaluation in the experimental autoimmune myasthenia gravis (EAMG) model. Monocytes were isolated and differentiated into moDCs to assess the effects of HMGB1 and its inhibitor, 18α-glycyrrhetinic acid (18α-GA), on the expression profiles, phenotypes, and functions of moDCs. Therapeutic efficacy was further assessed in EAMG using 18α-GA, HMGB1 neutralizing antibody, and adoptive transfer of 18α-GA-induced tolerogenic moDCs.</p><p><strong>Results: </strong>Mendelian randomization (MR) analyses revealed bidirectional causality between MG and moDCs. MG patients exhibited elevated plasma HMGB1 levels and mature phenotypes of moDCs. Mechanistically, HMGB1 activated the IRE1α/XBP1 and NF-κB pathways in moDCs through the engagement of TLR4, thereby inducing endoplasmic reticulum (ER) stress, promoting the activation of moDCs, and driving an imbalance in CD4+ T cell immune responses. Through a multitargeted mechanism of action, 18α-GA effectively inhibited both the IRE1α/XBP1 and NF-κB pathways in moDCs, thereby blunting ER stress and driving the differentiation of moDCs toward tolerogenic phenotypes. The minimal effective dose of 18α-GA alleviated EAMG by counteracting HMGB1-driven, moDC-mediated CD4+ T cell dysfunction, and showed better therapeutic performance compared with HMGB1 neutralizing antibody. Moreover, the adoptive transfer of 18α-GA-induced tolerogenic moDCs was effective in treating EAMG.</p><p><strong>Conclusions: </strong>HMGB1-mediated ER stress reprogrammed moDCs via the IRE1α/XBP1 and NF-κB pathways to promote pathogenic CD4+ T cell responses in MG. Targeting the HMGB1-ER stress axis in moDCs could restore immune balance and represent a promising therapeutic strategy for MG.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264866","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":"A brain-lung circuit drives LPS-induced lung injury via sympathetic neutrophil axis.","authors":"Shichun Ren, Shuo Yang, Baotong Liu, Qian Zhang, Zhenzhen Zhao, Yan Meng, Qi Shao, Xiaoming Deng, Jinjun Bian, Li Cao, Fengfeng Mo, Jiafeng Wang","doi":"10.1186/s12974-026-03914-z","DOIUrl":"10.1186/s12974-026-03914-z","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS) is a fatal complication of sepsis. However, the neural mechanisms underlying the exacerbation of pulmonary inflammation during systemic infection remain largely undefined. We employed an intraperitoneal lipopolysaccharide (LPS)-induced systemic inflammatory lung injury model and found that systemic inflammation strongly activates corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN), whereas bilateral subdiaphragmatic vagotomy abolished this response. Chemogenetic inhibition of CRH^PVN neurons alleviated lung injury and the formation of neutrophil extracellular traps (NETs), whereas chemogenetic activation of CRH^PVN neurons exacerbated pathological damage through sympathetic efferent signaling. Additionally, in patients with septic ARDS, β2-adrenergic receptor (ADRB2) expression was upregulated on neutrophils, and ADRB2 signaling delayed neutrophil apoptosis through the PI3K/Akt pathway, whereas ADRB2 blockade promoted neutrophil apoptosis and attenuated lung injury. In summary, we delineate a dysregulated neuroimmune axis in LPS-induced lung injury: systemic inflammatory signals activate the vagal afferent-PVN-sympathetic circuit, which in turn drives a neutrophil-mediated ADRB2-PI3K/Akt signaling pathway that amplifies lung injury. Our study reveals a mechanistic basis for neuroregulatory intervention and indicates that targeting this Brain-lung pathway may offer new therapeutic strategies for ARDS.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258505","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}