Journal of Neuroinflammation最新文献

{"title":"Microglial dynamics and neuroinflammation in prodromal and early Parkinson's disease.","authors":"Frida Lind-Holm Mogensen, Philip Seibler, Anne Grünewald, Alessandro Michelucci","doi":"10.1186/s12974-025-03462-y","DOIUrl":"10.1186/s12974-025-03462-y","url":null,"abstract":"<p><p>Parkinson's disease (PD) is characterized by a drastic loss of dopaminergic neurons already at diagnosis. As this loss of neurons starts decades before diagnosis, understanding the prodromal stages of the disease might offer novel strategies to curb its progression. While the precise pathogenic mechanisms underlying PD remain incompletely understood, growing evidence suggests that neuroinflammation and immune dysregulation play a central role in the development and progression of the disease. Here, we delve into the emerging roles of microglia, the resident immune cells of the central nervous system, in the pathogenesis of prodromal and early-stage PD. We emphasize that microglia contribute to neuroinflammation, protein aggregation and neurodegeneration, although the underlying mechanisms are not yet known. Neuroimaging studies have provided valuable insights into the patterns of microglial activation detected in individuals with prodromal PD and at the time of clinical diagnosis. Furthermore, we highlight the complex interplay between immune dysregulation and neurodegeneration along PD development, including alterations in the peripheral immune system, brain-gut interactions and brain-immune interfaces. Lastly, we outline existing models for investigating microglial involvement in prodromal PD, along with the impact of anti-inflammatory therapies and strategies to modify risk factors. In conclusion, targeting microglial activation and immune dysfunctions in individuals at risk of PD could represent a promising preventive measure and may offer novel therapeutic strategies for early intervention and disease modification.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"136"},"PeriodicalIF":9.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119905","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":"Caveolin-1 negatively regulates the calcitonin receptor-like receptor and neuroinflammation in a female mouse model of migraine.","authors":"Yanjie Zhou, Wu Chen, Yu Zhang, Liu Yang, Fu Lu, Wen Yan, Qingfang Xie, Ying Huang, Wanbin Huang, Lintao Wang, Ziming Zeng, Zheman Xiao","doi":"10.1186/s12974-025-03466-8","DOIUrl":"10.1186/s12974-025-03466-8","url":null,"abstract":"<p><strong>Background: </strong>Caveolin-1 (CAV1), a scaffolding protein critical for caveolae formation, regulates G-protein-coupled receptor (GPCR) signaling via caveolae-mediated endocytosis. The calcitonin receptor-like receptor (CLR), a GPCR and core subunit of the calcitonin gene-related peptide (CGRP) receptor, is a therapeutic target for migraine. However, the role of CAV1 in CLR regulation and migraine remains unclear.</p><p><strong>Methods: </strong>A migraine model was established in female mice via dural inflammatory soup (IS) application. Migraine-like behaviors were assessed using Von Frey filament, spontaneous pain behavior counts, light/dark box, and acetone test. CAV1 was overexpressed by lentivirus and downregulated by small interfering RNA (siRNA) technology. Methyl-β-cyclodextrin (MβCD) was used to inhibit caveolae-mediated endocytosis. The molecular mechanism of CAV1 on CLR and neuroinflammation was investigated using biochemistry, multiplex immunohistochemistry staining, internalization assay, and co-immunoprecipitation.</p><p><strong>Results: </strong>Repeated IS stimulation elevated CLR expression and internalization in the trigeminal nucleus caudalis (TNC), concurrently activating ERK/CREB signaling, promoting microglial activation, and increasing inflammatory cytokines (TNFα, IL-1β). CAV1 directly interacted with CLR, promoting its degradation. CAV1 knockdown in the TNC exacerbated migraine pathology, characterized by CLR accumulation, enhanced ERK/CREB phosphorylation, and amplified neuroinflammation. Conversely, CAV1 overexpression or MβCD-mediated caveolae disruption normalized CLR levels, reduced signaling hyperactivity, and reversed nociceptive behaviors.</p><p><strong>Conclusion: </strong>CAV1 negatively regulates CLR stability, suppressing ERK/CREB signaling and microglial inflammation in a preclinical female migraine model. These findings suggest that CAV1 contributes to migraine-related hyperalgesia and may represent a novel therapeutic target for migraine treatment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"134"},"PeriodicalIF":9.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12093816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119903","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":"RiboTag-based RNA profiling uncovers oligodendroglial lineage-specific inflammation in autoimmune encephalomyelitis: implications for pathogenesis.","authors":"Yuhang Wang, Sudeep Ghimire, Ashutosh Mangalam, Zizhen Kang","doi":"10.1186/s12974-025-03463-x","DOIUrl":"10.1186/s12974-025-03463-x","url":null,"abstract":"<p><p>Oligodendroglial lineage cells (OLCs) are essential for myelination, remyelination and neuronal metabolic support, but recent evidence suggests they also play active roles in neuroinflammation. This study aimed to identify the inflammatory translatome of OLCs during the onset of experimental autoimmune encephalomyelitis (EAE), a widely used model for Multiple Sclerosis (MS), using RiboTag-based RNA sequencing. We crossed RiboTag mice with Olig2-Cre mice to obtain strain-specific expression of HA-tagged ribosomal protein Rpl22 in OLCs, enabling the isolation of ribosome-associated mRNA from these cells for sequencing by using HA beads. Compared to controls, 1,556 genes were upregulated and 683 were downregulated in EAE OLCs. Gene enrichment revealed elevated immune-related pathways, including cytokine signaling, interferon responses and antigen presentation, whereas downregulated genes were associated with myelination and neuronal development. Notably, significant expression of cytokines/chemokines and their receptors was detected in OLCs. Further investigations focused on the role of IFNGR and IFNAR in EAE pathogenesis. IFN-γ signaling in OLCs exacerbated EAE pathogenesis by enhancing antigen processing, presentation, and chemokine production (e.g., Ccl2, Ccl7). In contrast, IFN-β signaling appeared less critical. These findings highlight the inflammatory role of OLCs in EAE, suggesting OLCs as a potential therapeutic target for mitigating neuroinflammation in MS and related disorders.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"135"},"PeriodicalIF":9.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12093676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119906","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":"Rebamipide (Mucosta®), a clinically approved drug, alleviates neuroinflammation and dopaminergic neurodegeneration in a Parkinson's disease model.","authors":"Hye-Sun Lim, Jinyoung Park, Eunjeong Kim, Wonhwa Lee, Hwi-Yeol Yun, Seung Hoon Lee, Gunhyuk Park","doi":"10.1186/s12974-025-03461-z","DOIUrl":"10.1186/s12974-025-03461-z","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is characterized by dopaminergic neuron loss, neuroinflammation, and motor dysfunction. PD is a multifactorial disease, with neuroinflammation driven by NLRP3 inflammasome activation representing an important component of its pathological progression. Therefore, we aimed to evaluate the therapeutic potential of rebamipide (Mucosta®), a clinically approved anti-inflammatory agent, in PD by targeting the NLRP3 inflammasome. Specifically, we examined the effects of rebamipide on neuroinflammation, dopaminergic neuron preservation, and motor deficits using BV2 microglia cells and a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mouse model.</p><p><strong>Main body: </strong>Rebamipide alleviated microglial activation and downstream neuroinflammation by suppressing the NLRP3-NEK7 interaction, resulting in dopaminergic neuron protection in the MPTP-induced PD model. Rebamipide downregulated IL-1β levels in BV2 microglia cells treated with α-synuclein and MPP⁺. Molecular docking analysis revealed a high binding affinity between rebamipide and the NLRP3-NEK7 interaction interface. Surface plasmon resonance analysis confirmed the direct binding of rebamipide to NLRP3, with notable kinetic affinity, supporting its role as a novel NLRP3 inflammasome inhibitor. Rebamipide significantly downregulated IL-1β levels, microglial activation, and dopaminergic neuron loss in the MPTP mouse model by disrupting inflammasome activation. Rebamipide preserved dopamine levels in the striatum and improved motor deficits, including bradykinesia and motor coordination. The neuroprotective effects of rebamipide were neutralized in NLRP3 knockout mice, confirming the dependency of its action on NLRP3.</p><p><strong>Conclusion: </strong>Considering its established clinical use, this study supports repurposing rebamipide for treating PD and other NLRP3 inflammasome-driven neuroinflammatory diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"132"},"PeriodicalIF":9.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094087","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":"Spatiotemporal dynamic changes of meningeal microenvironment influence meningeal lymphatic function following subarachnoid hemorrhage: from inflammatory response to tissue remodeling.","authors":"Bingrui Zhu, Changming Liu, Ming Luo, Jiarui Chen, Sixuan Tian, Tiantong Zhan, Yibo Liu, Haocheng Zhang, Zhen Wang, Jianmin Zhang, Yuanjian Fang, Sheng Chen, Xiaoyu Wang","doi":"10.1186/s12974-025-03460-0","DOIUrl":"10.1186/s12974-025-03460-0","url":null,"abstract":"<p><strong>Background: </strong>Meningeal lymphatic vessels (mLVs) play a critical role in clearing erythrocytes from the subarachnoid space and immune cells from the brain parenchyma following subarachnoid hemorrhage (SAH). However, the drainage function of mLVs is impaired during the acute stage after SAH and gradually recovers in the subacute phase. We aimed to investigate the meningeal transcriptional response post-SAH and elucidate the dynamic influence of meningeal microenvironment on meningeal lymphatic function.</p><p><strong>Methods: </strong>We employed bioinformatics analysis of single-cell RNA sequencing and spatial transcriptomics to characterize the spatiotemporal dynamic changes in the early meningeal microenvironment post-SAH. In a mouse model of SAH, the early dynamic changes of the meningeal immune cells and the potential growth factor that promoted the early repair of the mLVs were further investigated and validated.</p><p><strong>Results: </strong>During the acute phase, myeloid cells early infiltrated the meninges and triggered inflammatory responses. In the subacute phase, the fibroblast population expanded significantly, contributing to tissue remodeling. The interplay between immune cells and fibroblasts regulated cell migration and phenotypic transition, potentially affecting the function of mLVs. Notably, placental growth factor (PGF) emerged as the most prominent ligand within the VEGF signaling pathway received by meningeal lymphatic endothelial cells (mLECs) post-SAH. This signaling event was associated with the early recovery of mLVs after acute immune responses.</p><p><strong>Conclusions: </strong>Our study revealed a spatiotemporal transformation of the meningeal microenvironment from an \"inflammatory response\" phase to a \"tissue remodeling\" phase following SAH. Monocyte-derived macrophages and self-recruiting neutrophils contributed to impairment of mLVs in the acute stage, while PGF might serve as a key factor promoting early meningeal lymphatic function repair following the inflammatory response. These findings provided novel insights into the cellular dynamics underlying mLVs dysfunction and recovery post-SAH.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"131"},"PeriodicalIF":9.3,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086289","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":"Inverted day-night feeding during pregnancy affects the brain health of both maternal and fetal brains through increasing inflammation levels associated with dysbiosis of the gut microbiome in rats.","authors":"Xinyue Wang, Xiangju Kong, Yibo Ding, Mengqing An, Xuan Zhu, Yue Guan, Yucun Niu","doi":"10.1186/s12974-025-03447-x","DOIUrl":"https://doi.org/10.1186/s12974-025-03447-x","url":null,"abstract":"<p><strong>Background: </strong>In both humans and rodents, inappropriate feeding times during pregnancy can cause maternal metabolic abnormalities, increasing the risk of neurodevelopmental disorders in both the mother and offspring. Using a rat model, this study investigates whether feeding only during the inactive phase in rats leads to anxiety-like behaviors and abnormal brain development in fetuses through gut microbiota imbalance.</p><p><strong>Methods: </strong>10-week-old female rats in the inactive-phase feeding group (IF group) were first trained for daytime feeding, ensuring that energy intake was statistically insignificant and different from that of the normal diet feeding group (ND group). They were then paired with male rats, and the previous feeding regimen was continued after pregnancy. Anxiety-like behavior was evaluated using the open-field test. Maternal caecal microbiota was analyzed using 16S rRNA sequencing. Enzyme-linked immunosorbent assay (ELISA) measured serum inflammation factors. RT-PCR was employed to assess mRNA levels of integrity genes and inflammatory cytokines in the maternal hippocampi, intestines, fetal brains, and placentae.</p><p><strong>Results: </strong>There were no statistically significant differences in energy intake or body weight gain between the IF and ND groups. In the open field test, dams in the IF group exhibited anxiety-like behavior, as indicated by fewer entries into and shorter duration in the central zone. Active-phase fasting elevated maternal serum inflammatory cytokine levels and impaired antioxidant capacity. It also increased intestinal permeability and induced gut microbiota dysbiosis, characterized by a decrease in Akkermansia and an increase in Dubosiella. Changes in the expression of intestinal circadian genes and elevated intestinal inflammatory cytokines were observed. Lipopolysaccharide (LPS) translocated into the maternal circulation, activated Toll-like receptor 4 (TLR 4), and passed through the compromised placental barrier into the fetal brain, leading to increased expression of inflammatory cytokines in the fetal brain.</p><p><strong>Conclusions: </strong>The misalignment between maternal feeding time and the biological clock during pregnancy disrupts the balance of the gut microbiota and peripheral rhythms. The impaired intestinal and placental barriers allow LPS from the gut to infiltrate the maternal hippocampus and fetal brain, increasing inflammation and impacting both maternal and fetal brain health.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"130"},"PeriodicalIF":9.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988778","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":"Gut microbiota and their influence in brain cancer milieu.","authors":"Bandari BharathwajChetty, Aviral Kumar, Pranav Deevi, Mohamed Abbas, Athba Alqahtani, Liping Liang, Gautam Sethi, Le Liu, Ajaikumar B Kunnumakkara","doi":"10.1186/s12974-025-03434-2","DOIUrl":"https://doi.org/10.1186/s12974-025-03434-2","url":null,"abstract":"<p><p>Microbial communities are not simply remnants of the past but dynamic entities that continuously evolve under the selective pressures of nature, reflecting the intricate and adaptive processes of evolution. The microbiota residing in the various regions of the human body has numerous roles in different physiological processes such as nutrition, metabolism, immune regulation, etc. In the zeal of achieving empirical insights into the ambit of the gut microbiome, the research over the years led to the revelation of reciprocal interaction between the gut microbiome and the cognitive functioning of the human body. Dysbiosis in the gut microbial composition disturbs the homeostatic cognitive functioning of the human body. This dysbiosis has been associated with various chronic diseases, including brain cancer, such as glioma, glioblastoma, etc. This review explores the mechanistic role of dysbiosis-mediated progression of brain cancers and their subtypes. Moreover, it demonstrates the regulatory role of microbial metabolites produced by the gut microbiota, such as short-chain fatty acids, amino acids, lipids, etc., in the tumour progression. Further, we also provide valuable insights into the microbiota mediating the efficiency of therapeutic regimens, thereby leveraging gut microbiota as potential biomarkers and targets for improved treatment outcomes.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"129"},"PeriodicalIF":9.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021694","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":"Ubiquitination-mediated upregulation of glycolytic enzyme MCT4 in promoting astrocyte reactivity during neuroinflammation.","authors":"Luting Yang, Chunqing Hu, Xiaowen Chen, Mengru Sun, Jie Zhang, Zhe Feng, Tingting Cui, Ruyi Zhu, Xin Zhang, Yanxin Xiao, Ye Gong, Yang Yang, Qian Zhang, Yaling Zhang, Yaping Yan","doi":"10.1186/s12974-025-03453-z","DOIUrl":"https://doi.org/10.1186/s12974-025-03453-z","url":null,"abstract":"<p><p>One of the histopathological hallmarks of neuroinflammatory diseases such as multiple sclerosis (MS) is the emergence of astrocyte reactivity. Accumulating evidence suggests that excessive glycolysis may lead to astrocyte reactivity and contribute to neuroinflammatory responses. However, the intricate mechanisms underlying astrocyte metabolic reprogramming towards glycolysis remain largely unknown. Here, we conducted in vitro experiments using primary astrocytes and in vivo studies in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS). We observed increased astrocytic expression of MCT4, a key glycolytic regulator, in EAE mice. MCT4 enhanced astrocyte reactivity through promoting glycolysis and proliferation, mediated primarily by activation of the NF-κB and c-Myc signaling pathways. Notably, we report a novel regulatory mechanism in which the E3 ubiquitin ligase TRIM7 regulates MCT4 levels via ubiquitination. In mice, blockade of astrocyte MCT4 expression by intracerebroventricular injection of lentivirus alleviated disease severity of EAE mice. The results suggest that targeting glycolysis, specifically through the inhibition of MCT4 expression, might be effective in reducing astrocyte reactivity, neuroinflammation and demyelination occurring in MS and relating neuroinflammatory diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"126"},"PeriodicalIF":9.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064046","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 expanded polyglutamine in ATAXIN1 results in a loss-of-function that exacerbates severity of Multiple Sclerosis in an EAE mouse model.","authors":"Gourango Talukdar, Lisa Duvick, Praseuth Yang, Brennon O'Callaghan, Gavin J Fuchs, Marija Cvetanovic, Harry T Orr","doi":"10.1186/s12974-025-03450-2","DOIUrl":"https://doi.org/10.1186/s12974-025-03450-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>Ataxin-1 (ATXN1) is a protein in which expansion of its polyglutamine tract causes the neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) via a gain-of-function. Wild type ATXN1 was recently shown to have a protective role in regulating severity of experimental autoimmune encephalomyelitis (EAE), a well-established mouse model for Multiple sclerosis (MS). This study further investigates the role of ATXN1 with an expanded polyglutamine tract in the context of MS using an EAE mouse model.</p><p><strong>Methods: </strong>Hemizygous Atxn1 (Atxn1^2Q/-) mice or f-ATXN1^146Q/2Q, heterozygous mice that have one copy of the endogenous mouse gene replaced with a polyQ expanded pathogenic human ATXN1 gene, were injected with myelin oligodendrocytes glycoprotein (MOG_35 - 55) peptide to induce EAE. Immunohistochemical and biochemical approaches were used to analyze the degree of demyelination, cell loss, axonal degeneration as well as detecting the activated immune cells and inflammatory cytokines upon EAE induction in Atxn1^2Q/- and f-ATXN1^146Q/2Q mice.</p><p><strong>Results: </strong>Our findings reveal that a loss-of-function of wild type Atxn1 in Atxn1^2Q/- and f-ATXN1^146Q/2Q mice significantly exacerbates the EAE symptoms, leading to increased demyelination, oligodendrocytes loss, heightened axon degeneration, and greater clinical disability in affected mice. Importantly, the data reveals that neurotoxic astrocytes are activated at acute stage of disease (PID-14) and at the chronic stage of disease (PID-30) neurotoxic astrocytes no longer show signs of activation. The data also demonstrated enhanced infiltration of immune cells into the lesions of mutant mice.</p><p><strong>Discussion: </strong>These results indicate that ATXN1 plays a protective role in modulating immune responses and maintaining neural integrity during MS. Importantly, expansion of the polyQ tract in ATXN1 results in a loss-of-function in ATXN1's ability to dampen the immune response. Understanding the functional role of ATXN1 in MS pathogenesis may open new avenues for therapeutic strategies aimed at mitigating disease progression.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"127"},"PeriodicalIF":9.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009581","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":"Diffuse traumatic brain injury induced stimulator of interferons (STING) signaling in microglia drives cortical neuroinflammation, neuronal dysfunction, and impaired cognition.","authors":"Jonathan M Packer, Samantha G Giammo, Lynde M Wangler, Amara C Davis, Chelsea E Bray, Jonathan P Godbout","doi":"10.1186/s12974-025-03451-1","DOIUrl":"https://doi.org/10.1186/s12974-025-03451-1","url":null,"abstract":"<p><p>Neuropsychiatric complications including depression and cognitive impairment develop, persist, and worsen in the years after traumatic brain injury (TBI), negatively affecting life and lifespan. Inflammatory responses mediated by microglia are associated with the transition from acute to chronic neuroinflammation after TBI. Moreover, type I interferon (IFN-I) signaling is a key mediator of inflammation during this transition. Thus, the purpose of this study was to determine the degree to which a microglia-specific knockout of the stimulator of interferons (STING) influenced TBI-induced neuroinflammation, neuronal dysfunction, and cognitive impairment. Here, microglial inducible STING knockout (CX₃CR1Cre/ERT2 x STING^fl/fl) mice were created and validated (mSTING^-/-). Diffuse brain injury (midline fluid percussion) in male and female mice increased STING expression in microglia, promoted microglial morphological restructuring, and induced robust cortical inflammation and pathology 7 days post injury (dpi). These TBI-associated responses were attenuated in mSTING^-/- mice. Increased cortical astrogliosis and rod-shaped microglia induced by TBI were independent of mSTING^-/-. 7 dpi, TBI induced 237 differentially expressed genes (DEG) in the cortex of functionally wildtype (STING^fl/fl) associated with STING, NF-κB, and Interferon Alpha signaling and 85% were attenuated by mSTING^-/-. Components of neuronal injury including reduced NeuN expression, increased cortical lipofuscin, and increased neurofilament light chain in plasma were increased by TBI and dependent on mSTING. TBI-associated cognitive tasks (novel object recognition/location, NOR/NOL) at 7 dpi were dependent on mSTING. Notably, the TBI-induced cognitive deficits in NOR/NOL and increased cortical inflammation 7 dpi were unaffected in global interferon-α/β receptor 1 knockout (IFNAR1) mice. In the final study, the RNA profile of neurons after TBI in STING^fl/fl and mSTING^-/- mice was assessed 7 dpi by single nucleus RNA-sequencing. There was a TBI-dependent suppression of cortical neuronal homeostasis with reductions in CREB signaling, synaptogenesis, and oxytocin signaling and increases in cilium assembly and PTEN signaling. Overall, mSTING^-/- prevented 50% of TBI-induced DEGs in cortical neurons. Collectively, ablation of STING in microglia attenuates TBI-induced interferon responses, cortical inflammation, neuronal dysfunction, neuronal pathology, and cognitive impairment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"128"},"PeriodicalIF":9.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997183","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}