Journal of Neuroinflammation最新文献

{"title":"Translational insights into Long-COVID: evaluation of preclinical animal models along the lung-brain-immune axis with focus on Golden Syrian Hamsters.","authors":"Narendra Kumar, Navya Khandavalli, Sean N Avedissian, Hitendra S Chand, Arpan Acharya, Siddappa N Byrareddy","doi":"10.1186/s12974-026-03928-7","DOIUrl":"10.1186/s12974-026-03928-7","url":null,"abstract":"<p><p>Long-COVID, also referred to as post-acute sequelae of COVID-19 (PASC), is a heterogeneous disorder encompassing more than 200 reported symptoms that commonly affect the respiratory and nervous systems. Emerging clinical evidence indicates that unresolved lung inflammation, vascular injury, and immune dysregulation drive sustained neuroinflammation and impaired neurocognitive function in Long-COVID patients. Given the ethical and logistical constraints of human studies, biologically relevant animal models are essential for understanding the mechanisms and for evaluating therapeutic strategies against Long-COVID. In this review, we synthesize current evidence from preclinical animal models of Long-COVID, with a particular emphasis on the Golden Syrian Hamsters. Golden Syrian Hamsters are naturally susceptible to SARS-CoV-2 infection without the need for genetic modification and recapitulate key features of human disease, including robust viral replication, pulmonary pathology, and inflammatory response during acute infection. Importantly, accumulating evidence demonstrates that Golden Syrian Hamsters develop persistent post-acute abnormalities along the lung-brain-immune axis, including impaired alveolar repair, fibrotic lung remodeling, neuroinflammation, viral or antigen persistence, and behavioral alterations that parallel core features of Long-COVID. We compare the strengths and limitations of Golden Syrian Hamsters with other commonly used pre-clinical animal models including mice, and non-human primates, highlighting differences in translational relevance, feasibility, and ability to model chronic lung-brain-immune axis dysfunction. While there are limitations, particularly regarding limited availability of immunological reagents and validated cognitive and behavioral assays, the Golden Syrian Hamsters offers a balanced and accessible platform for mechanistic studies of PASC. Overall, this review positions Golden Syrian Hamster as a robust translational model for investigating lung-brain-immune axis pathology in Long-COVID and for advancing the development of targeted therapeutic interventions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148330557","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":"IRF7 deficiency in myeloid cells results in increased disease severity and death during alphavirus encephalomyelitis despite intact expression of type I interferons.","authors":"Benjamin H Nguyen, Elise Stanley, Wanmin Dai, Elizabeth M Troisi, Diane E Griffin","doi":"10.1186/s12974-026-03936-7","DOIUrl":"10.1186/s12974-026-03936-7","url":null,"abstract":"<p><p>Alphaviruses are arthropod-borne pathogens that cause immune-mediated encephalomyelitis. The prototypic alphavirus, Sindbis virus (SINV), primarily infects neurons in mice, resulting in neurologic disease involving both the brain and spinal cord. Interferon (IFN) regulatory factor (IRF) 7-deficient mice (Irf7^-/-) rapidly succumb to SINV infection with extensive immunopathology while wildtype mice experience only mild disease and recover. IRF7 is widely recognized to be the main transcription factor required for the amplification of type I IFN, specifically IFNα, as Irf7^-/- mice do not produce IFNα but do express IFNβ. However, based on the current experimental evidence, it is not clear if the severe outcome of SINV infection in Irf7^-/- mice is due to the absence of IFNα or heretofore unappreciated noncanonical actions of IRF7. In this study, we demonstrate that the administration of IFNα to Irf7^-/- mice early in infection restricted SINV replication and largely rescued the animals from severe disease and mortality but did not alter the nature of CNS inflammation. Further, Cre-Lox-mediated deletion of Irf7 in myeloid cells (Irf7^fl/flLyz2-cre mice) resulted in severe disease and lethality despite significantly higher peak levels of IFNα than WT animals, suggesting that the lethal phenotype of Irf7^-/- mice was attributed to the myeloid cell-specific loss of IRF7 and not to the loss of IFNα production. Both Irf7^-/- and Irf7^fl/flLyz2-cre mice had increased levels of monocytes infiltrating into the brain compared to WT, indicating a potential role for IRF7 in the trafficking and activation of myeloid cells. Therefore, while IFNα supplementation may contribute to reducing disease severity by restricting virus replication, disease was ultimately exacerbated by the increased infiltration of inflammatory myeloid cells in Irf7^-/- mice.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317342","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":"An irradiation-free platform for localized skull bone marrow manipulation to dissect the skull-brain axis.","authors":"Yi Lv, Jinmeng Yi, Dongmei You, Yuan Yan, Bo Tang, Yiguo Qiu, Yuzhang Wu","doi":"10.1186/s12974-026-03906-z","DOIUrl":"10.1186/s12974-026-03906-z","url":null,"abstract":"<p><p>The skull bone marrow (SBM) has recently emerged as a crucial regulator of brain physiology and pathology. However, its direct impact on the brain remains elusive, as existing methods cannot isolate local SBM functions from systemic confounds. Here, we developed an irradiation-free cranial bone flap transplantation platform that enables localized SBM replacement and niche-preserving engraftment. Our method establishes exclusive chimerism within CNS compartments, achieving a \"peripherally clean\" profile that cleanly separates SBM-brain communication from systemic variables. Comprehensive characterization of this model revealed age- and sex-dependent chimerism patterns specifically within central nervous system (CNS) niches. In contrast to conventional long bone marrow (LBM) transplantation, our model achieved robust CNS-targeted engraftment with minimal peripheral involvement. Proof-of-concept functional studies further demonstrated its functional utility by attenuating brain aging and neuroinflammation through young SBM transplantation into old recipients. Our model provides a targeted approach to dissect the skull-brain axis in health and disease, opening avenues to decipher its role in neurological disorders and to identify niche-specific therapeutic targets.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148330533","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":"Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.","authors":"Yuta Morisaki, Nanaka Nomura, Motoki Ohshima, Miruto Matsuda, Okiru Komine, Takashi Okuda, Koji Yamanaka, Hidemi Misawa","doi":"10.1186/s12974-026-03919-8","DOIUrl":"10.1186/s12974-026-03919-8","url":null,"abstract":"<p><p>Immune checkpoint molecules, inhibitory receptors originally characterized in T cell biology, have recently emerged as regulators of microglial function in neurodegeneration, yet their roles in amyotrophic lateral sclerosis (ALS) remain unexplored. Here, we investigated LAG-3, an inhibitory immune checkpoint receptor, in microglial regulation during ALS pathogenesis using SOD1^G93A mice. LAG-3 expression was progressively upregulated in spinal cord microglia during disease progression, and LAG-3-high microglia exhibited a disease-associated microglia (DAM) transcriptional signature. Genetic deletion of LAG-3 produced a biphasic phenotype, with accelerated disease onset but significantly prolonged disease duration. LAG-3 deficiency enhanced inflammatory microglial responses at the early disease stage, whereas at the late stage it suppressed inflammatory signaling while selectively preserving phagocytic effector gene expression, demonstrating that LAG-3 dissociates the inflammatory and phagocytic modules within the DAM program in a stage-dependent manner. These transcriptional changes translated into enhanced phagocytic capacity in primary microglia and amelioration of the spinal cord environment through suppression of inflammatory pathways and restoration of oxidative phosphorylation. Our findings identify LAG-3 as a stage-dependent regulator of microglial functional states in ALS and support the concept that immune checkpoint molecules constitute a class of module-level regulators of microglial function in neurodegeneration.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317287","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":"Multi-dimensional decoding of the TSPO signal in animal models of neuroinflammation using fluorescence-conjugated DPA714.","authors":"Huanhuan Song, Zhibao Zhu, Limei Xiao, Qiuping Zhao, Chun Li, Aowei Lv, Xintong Yu, Zhuyu Gao, Jie Lin, Youliang Wang, Yuanyuan Zhang, Lijie Zhang, Runyun Li, Shaobo Yao, Mengchao Cui, Yi Lin, Ying Fu, V Wee Yong, Rui Li","doi":"10.1186/s12974-026-03829-9","DOIUrl":"10.1186/s12974-026-03829-9","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317477","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":"Extracellular vesicles from plasma of patients with minimal hepatic encephalopathy induce neuroinflammation and cognitive impairment in rats, which are prevented by treating the patients with rifaximin.","authors":"Adria Lopez-Gramaje, Yaiza M Arenas, Juan-José Gallego, Paula Izquierdo-Altarejos, Amparo Urios, Desamparados Escudero-García, Salvador Benlloch, Elena Kosenko, Vicente Felipo, Carmina Montoliu","doi":"10.1186/s12974-026-03922-z","DOIUrl":"10.1186/s12974-026-03922-z","url":null,"abstract":"<p><p>Minimal hepatic encephalopathy (MHE) appearance is associated with a pro-inflammatory shift in peripheral inflammation. Treatment of MHE patients with rifaximin reverses this shift in and improves MHE. How peripheral alterations are transmitted to brain to induce MHE remains unclear. In rats with MHE, plasma extracellular vesicles (EV) induce cognitive impairment. We hypothesized that in cirrhotic patients, the shift in peripheral inflammation is associated with alterations in plasma EV which contribute to induce MHE in cirrhotic patients. We also hypothesized that rifaximin treatment reverses MHE by reversing changes in EV. The aims were: 1) assess if injecting rats with plasma EV from MHE patients (MHE-EV) induce cognitive impairment, 2) identify the underlying mechanisms, 3) assess if treating MHE patients with rifaximin reverses the pathological effects of their EV and, 4) if this is associated with reversal of changes in EV protein cargo. We isolated plasma EV from cirrhotic patients without and with MHE, treated or not with rifaximin, and controls and injected them to rats. We analysed cognitive function, neuroinflammation and glutamate receptors membrane expression in hippocampus. MHE-EV, but not EV from patients without MHE show increased TNFα content and trigger a strong cognitive impairment in rats. This is mediated by altered membrane expression of AMPA and NMDA glutamate receptors in hippocampus, due to increased neuroinflammation, with glial activation and enhanced activation of the TNFα-TNFR1-S1PR2-IL-1β-IL-1R pathway. The EV from MHE patients treated with rifaximin did not show increased TNFα levels and did not induce the above pathological effects. Rifaximin treatment reverses the changes in the cargo of the EV from plasma of MHE patients, including the increase in TNFα and eliminates the pathological effects of the EV. The data show that in cirrhotic patients the presence of MHE is associated with changes in their blood EV which transmit pathological effects to the brain, inducing neuroinflammation and altered glutamatergic neurotransmission in hippocampus which leads to cognitive impairment. Rifaximin treatment reduces TNFα and other altered proteins in the EV and reverses their pathological effects. EV could be a therapeutic target to improve MHE by modifying EV content or blocking the TNFα effects.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317325","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":"Complement C5a/C5aR1 pathway facilitates glioblastoma progression via fostering glioma stem cell-macrophage symbiosis.","authors":"Hongtao Zhu, Lidong Cheng, Dan Liu, Yixuan Ma, Heng Fan, Shuting He, Wenjia Liang, Daluo Mei, Xiaoyu Ma, Ran Li, Hailong Mi, Junwen Wang, Jun Li, Xingjiang Yu, Suojun Zhang, Kai Shu","doi":"10.1186/s12974-026-03930-z","DOIUrl":"10.1186/s12974-026-03930-z","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) symbiotically interact with glioma stem cells (GSCs) to facilitate GSCs stemness maintenance and glioblastoma (GBM) progression. Here we identified the complement 5a (C5a) as a key mediator of GSCs-TAMs symbiosis through integrative screening. C5a is preferentially expressed and secreted by GSCs. C5a activates the p-STAT3-cMyc-PD-L1 axis to promote GSCs proliferation, self-renewal and resistance against cytotoxic T cells through its receptor C5aR1. Moreover, GSCs-derived C5a trigger the infiltration and immunosuppressive polarization of TAMs through C5aR1-p-AKT T308 axis in tumor microenvironment. Importantly, silencing or pharmacological inhibition of C5a/C5aR1 disrupts both GSCs and TAMs and suppresses GBM tumor growth. In human GBM, the C5a/C5aR1 axis is activated and positively correlates with stemness, immunosuppressive TAMs and predicts poor prognosis. Collectively, these results demonstrate the key role of C5a/C5aR1 pathway in GSCs-TAMs symbiosis and indicate the therapeutic potential of targeting this pathway for GBM treatment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317321","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":"Bortezomib-induced gastrointestinal dysfunction, peripheral neuropathy and neuroimmune signalling are influenced by the gut microbiota in mice.","authors":"Jacqui S Scott, Sadia Munir, Miriam A Lynn, Jvaughn A Duggan, Joel Castro, Andrea M Harrington, Stuart M Brierley, Gudrun Schober, Kathy Cash, Bernice Gutschmidt, Mark R Hutchinson, Angelina Yong, Samuel P Costello, Suranjana Sikdar, Pawanrat Tangseefa, Duncan R Hewett, Courtney B Cross, Susanna B Park, Feargal J Ryan, Andrew C W Zannettino, David J Lynn, Kate Vandyke, Hannah R Wardill, Krzysztof M Mrozik","doi":"10.1186/s12974-026-03909-w","DOIUrl":"10.1186/s12974-026-03909-w","url":null,"abstract":"<p><strong>Background: </strong>Peripheral neuropathy and gastrointestinal dysfunction are frequent, debilitating side effects of the neurotoxic myeloma drug bortezomib that reduce quality of life and adherence to optimal therapy. Therapeutic strategies to manage these complications are limited. Here, we have developed a mouse model of bortezomib side effects to investigate the role of the gut microbiota in their development.</p><p><strong>Methods: </strong>C57BL/6 specific pathogen-free (SPF), germ-free (GF) and ex-GF mice (colonised with healthy gut microbiota via faecal microbiota transplantation [FMT]) were treated with bortezomib (1 mg/kg) twice-weekly for two weeks. Neurotoxicity and neuroimmune signalling were assessed by serum neurofilament light chain (NfL) quantitation and real-time qPCR analysis of inflammatory markers in sensory and autonomic nerve ganglia, respectively. Faecal microbiota composition was characterised using 16S rRNA gene sequencing. Bortezomib side effects were assessed using behavioural phenotyping, von Frey mechanical sensitivity and rotarod testing, and FITC-dextran gut permeability and Evans Blue dye transit assays.</p><p><strong>Results: </strong>Bortezomib-treated SPF mice displayed altered spontaneous behaviour and developed acute gastric retention, altered gastrointestinal motility and increased intestinal permeability, in the absence of intestinal micro-architecture changes. Concurrently, bortezomib induced sensory loss in, and increased grooming of, paws, and reduced motor performance, indicative of peripheral neuropathy. Bortezomib neurotoxicity was evidenced by elevated serum NfL levels and neuroimmune signalling in sciatic nerve dorsal root and vagal nerve nodose ganglia. In SPF mice, bortezomib altered gut microbiota composition with an acute decrease in microbial diversity and expansion of Lactobacillus gasseri. Notably, GF mice developed a milder symptom profile following bortezomib treatment compared with SPF mice, while FMT mice did not develop overt bortezomib side effects despite displaying evidence of nerve damage.</p><p><strong>Conclusions: </strong>This is the first study to model gastrointestinal side effects of bortezomib in rodents, implicating neuroimmune dysregulation of the vagus nerve. Our data show that the gut microbiota is not a primary driver of bortezomib side effects. However, the absence of a symptom profile in FMT mice suggests that, in GF mice, the gut microbiota beneficially modulates the host to protect against bortezomib side effects. Further studies are required to determine whether this can be harnessed to mitigate clinical complications of bortezomib.</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/PMC13551697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308489","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":"Immunopathogenesis of neuropsychiatric systemic lupus erythematosus: current insights into inflammatory and thrombotic pathways.","authors":"Igor Adamski, Anna Wardowska","doi":"10.1186/s12974-026-03920-1","DOIUrl":"10.1186/s12974-026-03920-1","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance, systemic inflammation, autoantibody production, and immune complex formation. Neuropsychiatric systemic lupus erythematosus (NPSLE) represents one of the most severe manifestations of the disease and may involve both the central and peripheral nervous systems. Its pathogenesis remains incompletely understood and reflects the interplay among systemic immune dysregulation, vascular injury, blood-brain and blood-CSF barrier dysfunction, and local neuroinflammatory processes.Current evidence supports two partially overlapping pathogenic pathways: an autoimmune-inflammatory and a thrombo-ischemic pathway. These mechanisms promote disruption of the blood-brain barrier, infiltration of immune cells into the central nervous system, activation of microglia, and neuronal dysfunction. Increasing evidence also highlights the role of neutrophil extracellular traps, complement activation, type I interferon signaling, and autoreactive lymphocytes in driving neuroinflammation.The heterogeneity of clinical manifestations and the diversity of underlying mechanisms make NPSLE a major diagnostic and therapeutic challenge. This review summarizes current knowledge on the immunopathogenesis of NPSLE, with particular attention to the strength of evidence supporting individual mechanisms. Human clinical studies provide important associative data, whereas animal models and cell-based systems offer mechanistic insight into selected pathways. We also discuss emerging biomarkers, limitations of current evidence, and potential therapeutic targets that may improve future diagnosis, stratification, and management of NPSLE.</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/PMC13543638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308454","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":"PDZD8 overexpression alleviates early brain injury via regulating MERCs integrity after experimental subarachnoid hemorrhage.","authors":"Peng Deng, Xin Wu, Yangyang Liu, Bingyi Song, Xi Liu, Xiao Yang, Han Luo, Jiabei Peng, Haiying Li, Zhong Wang, Zongqi Wang, Wen Li","doi":"10.1186/s12974-026-03931-y","DOIUrl":"10.1186/s12974-026-03931-y","url":null,"abstract":"<p><p>Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disorder with high acute mortality and long-term neurological disability, and early brain injury (EBI) characterized by mitochondrial dysfunction, oxidative stress, and neuronal apoptosis is a pivotal determinant of poor prognosis. Mitochondria-endoplasmic reticulum contact sites (MERCs) are specialized membrane domains essential for maintaining cellular homeostasis via calcium trafficking and lipid exchange, but their regulatory mechanisms in SAH-induced EBI remain largely undefined. Here, we investigated the role and underlying mechanism of PDZD8, a core MERCs-stabilizing protein, in SAH pathogenesis using in vivo endovascular perforation models of male C57BL/6 mice and in vitro oxyhemoglobin (OxyHb)-challenged primary cortical neurons/HT22 cells, combined with PDZD8 overexpression, CRISPR/Cas9-mediated knockout, and C884A site-directed mutagenesis. Results demonstrated that PDZD8 was neuron-specifically downregulated at 48 h post-SAH, which closely correlated with MERCs structural disruption detected by transmission electron microscopy, impaired mitochondrial respiration analyzed via Seahorse assays, excessive reactive oxygen species production, and severe neuronal damage assessed by Nissl staining. PDZD8 overexpression preserved MERCs integrity, restored mitochondrial metabolic balance, mitigated oxidative stress, and ameliorated neurobehavioral deficits evaluated by modified neurological severity scores, rotarod, and open field tests. Mechanistically, SAH-induced PDZD8 downregulation was associated with enhanced global S-nitrosylation and post-translational regulation at cysteine 884 (C884), promoting its ubiquitination and proteasomal degradation, while C884A mutation abrogated this process. Our findings reveal a previously unrecognized mechanism involving S-nitrosylation-associated ubiquitination of PDZD8 in SAH-induced MERCs dysfunction and EBI, highlighting PDZD8 as a promising therapeutic target for SAH treatment.</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/PMC13543607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308525","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}