Journal of Neuroinflammation最新文献

{"title":"SARS-CoV-2 infection is associated with hypothalamic orexin suppression and persistent cortical NeuN attenuation.","authors":"Gun Young Yoon, Young Cheul Chung, Ji Hyun Choi, Yun Ha, Se Yeon Seo, Keun Bon Ku, Do Yeon Kim, Woo Yeon Hwang, Gi Uk Jeong, Dae-Gyun Ahn, Kyun-Do Kim, Je-Keun Rhee, Won-Ho Shin, Young-Chan Kwon","doi":"10.1186/s12974-026-03842-y","DOIUrl":"https://doi.org/10.1186/s12974-026-03842-y","url":null,"abstract":"<p><p>Long COVID frequently presents with persistent neurological symptoms, including cognitive impairment, fatigue, and sleep disturbances; however, its underlying mechanisms remain unclear. Here, we show that SARS-CoV-2 infection induces lasting cortical neuronal injury and hypothalamic orexin (hypocretin) dysfunction in vivo. In K18-hACE2 and wild-type BALB/c mice, viral RNA persisted in the brain and coincided with focal loss of Neuronal Nuclei (NeuN)-positive cortical neurons beyond acute infection. SARS-CoV-2, but not the influenza A virus, triggered rapid and sustained suppression of hypothalamic orexin expression, defining a virus-specific neuropathological signature. Considering the downregulation of orexin and focal cortical NeuN attenuation, we found that exogenous orexin-A/B supplementation increased NeuN abundance in vitro and in vivo under the tested conditions. Overall, these findings identify the orexin system as a candidate neural vulnerability to SARS-CoV-2 and suggest that orexinergic dysfunction may contribute to the neurological manifestations of Long COVID.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An unrecognized mechanism of neuroprotection by microglial TIA1-mediated stress granules to prevent neuroinflammation and demyelination in experimental autoimmune encephalomyelitis mice through sequestering ApoE mRNA.","authors":"Qinjiao Fu, Yanzhu Liu, Fangfang Li, Yanjiao Wang, Juanqing Yue, Yingyi Chen, Shufang Wu, Jingjing Zhang, Mengxian Jia, Yaozhi He, Jiawei Wang, Zhihui Huang, Ying Wang","doi":"10.1186/s12974-026-03833-z","DOIUrl":"https://doi.org/10.1186/s12974-026-03833-z","url":null,"abstract":"<p><p>Microglia contribute to the pathogenesis of multiple sclerosis (MS) by promoting inflammatory cascades, mediating demyelination and regulating autoimmune responses, however, the molecular mechanisms connecting cellular stress to microglia-mediated immune responses in MS remain elusive. Stress granules (SGs) serve as an adaptive response of cells to various stressors such as viral infection and oxidative stress. In this study, we found that microglial T-cell intracellular antigen 1 (TIA1), a core SG component, was upregulated in MS patients and experimental autoimmune encephalomyelitis (EAE) mice. The neuroinflammation, demyelination and clinical deficits were exacerbated in Tia1^Cx3cr1-CKO (TIA1 knockout in microglia and monocyte-derived macrophages) EAE mice. Furthermore, TIA1^-/- microglia exhibited the heightened activation characterized by increased proliferation, enhanced phagocytic activity, and a sustained polarization toward a pro-inflammatory phenotype. Notably, in an in vitro model of NaAsO₂-induced stress, TIA1 deficiency in BV2 cells and primary cultured microglia resulted in both enhanced phagocytic capacity and a pro-inflammatory phenotypic shift. Mechanistically, upon to stresses, microglial TIA1-mediated SGs formation was enhanced, leading to sequester ApoE mRNA into SGs to reduce ApoE expression, which in turn prevented excessive activation of microglia and inhibited demyelination in EAE mice. These findings uncover a previously unrecognized neuroprotective mechanism wherein TIA1-mediated SGs in microglia dynamically restrain neuroinflammation via post-transcriptional control of ApoE, revealing a new therapeutic avenue for MS.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feasibility of multimodal metabolic analysis for detecting early changes in acute neuroinflammation.","authors":"James T Grist, Ilia Evstafev, Dominika Olesova, Signe E Nynäs, Matej Orešič, Alex M Dickens, Damian J Tyler, Yvonne Couch","doi":"10.1186/s12974-026-03839-7","DOIUrl":"https://doi.org/10.1186/s12974-026-03839-7","url":null,"abstract":"<p><p>Given the prevalence of metabolic perturbations in a variety of neurological and neurodegenerative diseases, understanding and monitoring brain metabolism is a key step in our advancement of therapies. The details of the citric acid cycle were established at the beginning of the last century but only recently have its metabolic intermediates been observed in vivo in the brain. In this study, we employed orthogonal analyses to investigate metabolic alterations in response to acute neuroinflammation in vivo, demonstrating a multi-technique approach that could be used for future studies.Hyperpolarized [1-¹³C] pyruvate spectroscopy revealed an early decline in pyruvate metabolism via pyruvate dehydrogenase (PDH), leading to reduced ¹³C-bicarbonate formation. This metabolic disruption occurred despite the absence of structural or perfusion changes on conventional MRI. Further analysis of polar metabolites in the ipsilateral hemisphere confirmed ongoing inflammatory processes. These findings highlight the potential of this dual technique approach to inform upon metabolic changes due to neuroinflammation.Combining methods to probe metabolism in invasive (metabolomics) and non-invasive (hyperpolarized MRI) manners, this represents a promising translational approach for real-time metabolic assessments in an area of the body, the brain, where studying processes such as metabolism has traditionally been challenging. This study has demonstrated the approach to monitor changes in metabolism in response to inflammation in the brain.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer's disease.","authors":"Verónica López-López, Gerard Iniesta, Marcos Galán-Ganga, Alejandro Expósito-Coca, Violeta Durán-Laforet, Aysha M Bhojwani-Cabrera, Carmen M Navarrón, Marina Guillot-Fernández, Jose L Venero, Jose V Sánchez-Mut, Angel Barco, Albert Giralt, José P López-Atalaya","doi":"10.1186/s12974-026-03840-0","DOIUrl":"https://doi.org/10.1186/s12974-026-03840-0","url":null,"abstract":"<p><p>Alzheimer's disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of postmortem AD tissue and APP/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The meningeal lymphatic vessel-peripheral immune axis: a novel therapeutic target in neurodegenerative diseases.","authors":"Zhidong He, Jing Sun","doi":"10.1186/s12974-026-03849-5","DOIUrl":"https://doi.org/10.1186/s12974-026-03849-5","url":null,"abstract":"<p><p>Meningeal lymphatic vessels serve as a direct anatomical conduit connecting the central nervous system and the peripheral immune system, fundamentally challenging the traditional view of the brain as an \"immune-privileged\" organ. This review systematically examines, for the first time, the meningeal lymphatic vessel-peripheral immune axis as an integrated framework linking central proteinopathy, neuroinflammation, and systemic immune responses in neurodegenerative diseases. We highlight recent therapeutic advances, including lymphatic regeneration via the VEGF-C pathway, peripheral immune modulation, and combinatorial approaches. We also discuss current challenges and future translational directions, emphasizing the need for integrating lymphatic imaging with immune phenotyping to enable personalized interventions. While the majority of evidence discussed derives from preclinical models, we critically evaluate its translational relevance and highlight unresolved controversies. Based on the evidence, we propose that targeting this axis offers a dual opportunity to enhance CNS waste clearance and restore immune tolerance, providing a promising framework for clinical management.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Omega-3 polyunsaturated fatty acid attenuates traumatic brain injury-induced neuronal apoptosis by inducing autophagy through the upregulation of SIRT1-mediated deacetylation of Beclin-1.","authors":"Xiangrong Chen, Zhigang Pan, Zhongning Fang, Weibin Lin, Shukai Wu, Fuxing Yang, Yasong Li, Huangde Fu, Hongzhi Gao, Shun Li","doi":"10.1186/s12974-026-03816-0","DOIUrl":"https://doi.org/10.1186/s12974-026-03816-0","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816263","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":"Acarbose modulates microglial Pkm2 acetylation to reshape immunometabolism and preserve retinal neurons after ischemia-reperfusion.","authors":"Yuwen Wen, Ya-Nan Dou, Xiaohong Chen, Xiuxing Liu, Zhenlan Yang, Yingting Zhu, Zhidong Li, Caibin Deng, Ye Deng, Wenru Su, Yehong Zhuo","doi":"10.1186/s12974-026-03838-8","DOIUrl":"https://doi.org/10.1186/s12974-026-03838-8","url":null,"abstract":"<p><p>Retinal ischemia-reperfusion (IR) elicits microglia-driven neuroinflammation and mitochondrial failure that led to retinal ganglion cell (RGCs) loss, yet effective disease-modifying therapies remain limited. Acarbose (ACA), an α-glucosidase inhibitor widely used for diabetes, has recently been recognized for its dual regulatory potential on immune metabolism and aging-associated neurodegeneration. Here, we demonstrate that intravitreal ACA administration attenuates retinal inflammation and improves RGCs survival following IR injury. Single-cell RNA sequencing revealed extensive inflammatory activation and metabolic reprogramming across the retina, characterized by enhanced nicotinamide adenine dinucleotide (NAD) catabolism, particularly in microglia. ACA treatment was associated with reversal of these alterations, replenished NAD levels, and restored mitochondrial integrity. Integrative proteomic and biochemical analyses identified pyruvate kinase, muscle-type 2 (Pkm2) as a candidate regulatory node affected by ACA. Intravitreal delivery of siPkm2 partially protected against IR injury, and co-administration with ACA produced an additive trend in neuroprotection. Mechanistically, ACA upregulated sirtuin 1 (Sirt1) and reduced Pkm2 acetylation at lysine 270 (K270), which was linked to pro-inflammatory microglial activation. Structure-based virtual screening further identified HY-113082, a small molecule targeting Pkm2-K270, which synergized with ACA to suppress inflammation and enhance retinal protection. Moreover, Pkm2^fl/flCx3cr1-Cre mice conferred partial resistance to IR injury, but blunted the additional benefit of HY-113082 when combined with ACA, consistent with on-target engagement. Our findings support that ACA exerts retinal protection through the Sirt1-Pkm2-NAD axis, suggesting a metabolic checkpoint that integrates immune and mitochondrial regulation. This study provides mechanistic insight into ACA's dual immunometabolic and neuroprotective actions, holding promise for therapeutic insights into neuroinflammation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALS-FTD-linked CCNF^S621G drives increased hippocampal astrocyte ramification and mitochondrial dysfunction and impairs motor neuron excitability.","authors":"Liam Robinson, Dzung Do-Ha, Flora Cheng, Claire H Stevens, Rossana Rosa Porto, Madilyn Coles, Jamesha Subachandran, Predrag Kalajdzic, Joanna Lui, Rachelle Balez, Sonia Sanz Muñoz, Mauricio Castro Cabral-da-Silva, Tracey Berg, Marco Morsch, Leszek Lisowski, Rachel H Tan, Gaétan Burgio, Tim Karl, Albert Lee, Roger S Chung, Ian Blair, Lezanne Ooi","doi":"10.1186/s12974-026-03827-x","DOIUrl":"https://doi.org/10.1186/s12974-026-03827-x","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping pathology. Mutations in CCNF, encoding the E3 ubiquitin ligase, Cyclin F, can cause ALS, FTD, or both, even within the same family. Most prior studies of CCNF^S621G have relied on overexpression systems, potentially confounding outcomes through disruption of endogenous Cyclin F. Here, we generated the first knock-in mouse model of endogenous Ccnf^S621G using CRISPR/Cas9. Heterozygous and homozygous Ccnf^S621G mice showed no motor decline or neuronal loss after 18 months, however immunohistochemistry revealed increased hippocampal astrocyte ramification, with sex-, age, and subfield-dependent effects. These data indicate that endogenous Ccnf^S621G may prime early astrocyte alterations in the absence of overt neurodegeneration. Similar astrocyte morphological changes were observed in canonically affected regions of sporadic ALS and FTD-ALS patients post mortem, as well as in CCNF^S621G iPSC-derived astrocytes following inflammatory stimulation. Proteomics on Ccnf mice identified early dysregulation of pathways related to translation, mitochondrial function, cytoskeletal remodelling, synaptic transmission and neuroinflammation. Correspondingly, CCNF^S621G iPSC-derived astrocytes displayed impaired mitochondrial membrane potential and altered network morphology under both basal and inflammatory stimuli. As altered neuronal excitability is a hallmark of ALS, we examined astrocyte-driven changes to neuronal excitability. CCNF^S621G iPSC-derived motor neurons cultured alone were hyperexcitable, firing more action potentials than isogenic controls. Remarkably, co-culture with CCNF^S621G astrocytes, but not isogenic control astrocytes, abolished repetitive firing, increased the proportion of neurons unable to generate action potentials, and reduced voltage-gated sodium currents in CCNF^S621G and isogenic control neurons. Together, these findings identify astrocyte alterations as an early feature of CCNF^S621G-mediated disease, in the absence of neuronal loss. Moreover, the combination of astrocytic mitochondrial dysfunction and the ability of CCNF^S621G astrocytes to suppress repetitive neuronal firing suggests a critical astrocyte-driven non-cell autonomous mechanism that may contribute to an oligogenic role for CCNF in ALS/FTD pathogenesis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147815485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired suppressive effect of FoxP3 regulatory T cells on B cells in multiple sclerosis.","authors":"Viktoria B Greeck, Cornelia Würthwein, Karina Mimura, Katharina Mattes, Michael Kutza, Lucas Schirmer, Richard Fairless, Sarah K Williams, Sven Jarius, Jürgen Haas, Klemens Ruprecht, Brigitte Wildemann","doi":"10.1186/s12974-026-03776-5","DOIUrl":"https://doi.org/10.1186/s12974-026-03776-5","url":null,"abstract":"<p><strong>Background: </strong>B cells are key contributors to the pathogenesis of many autoimmune diseases (AID), including multiple sclerosis (MS), and appear to evade the peripheral tolerance checkpoints that normally maintain immune homeostasis. The fate of B cells at these checkpoints is believed to be regulated by intracellular Ca²⁺ signaling cascades triggered through engagement of B cell receptors (BCR), and by the suppressive effects of regulatory T cells (Tregs). However, most of the current knowledge about Treg-B cell interaction comes from animal studies, while data from human studies, particularly in the context of AID, are sparse. In contrast, impaired Treg-mediated inhibition of conventional T cells (Tcons) has already been described for several AID, including MS.</p><p><strong>Objective: </strong>To assess the ability of Tregs to suppress activated B cells in healthy individuals and patients with MS.</p><p><strong>Methods: </strong>B and T cell populations were isolated from 40 MS patients and 98 age- and sex-matched healthy donors (HD). Single-cell live Ca²⁺ imaging was used to assess early activation signals in B cells. In vitro proliferation assays and coculture experiments were employed to evaluate downstream responses, including proliferation, transcription factor activation (NFATc1, NF-ĸB), interleukin 6 (IL-6) release, and surface expression levels of antigen-presenting capacity (APC) markers both in anti-IgM/anti-CD40-stimulated B cells alone, and in the presence of Tregs.</p><p><strong>Results: </strong>We demonstrate that Tregs exert a robust suppressive effect on B cell proliferation, IL-6 secretion and NFATc1 which is [1] independent of Ca²⁺ signaling [2], dependent on direct cell contact, and [3] impaired in MS. In contrast, early Ca²⁺ responses and downstream effects of anti-IgM/anti-CD40 stimulation, including activation of NFATc1 and NF-κB, as well as proliferation, did not differ between MS- and HD-derived B cells.</p><p><strong>Conclusion: </strong>This study provides new data on Treg-mediated suppression of B cells in humans, including at single-cell level. Our findings show that the Treg dysfunction in MS previously described in the context of Tcon regulation extends to B cell regulation. Given the critical role of B cells in MS pathogenesis, this impaired Treg-B cell interaction may represent a previously underappreciated disease mechanism with potentially important therapeutic implications.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Piezo1 in the central nervous system: decoding the mechanical signature of neuroinflammation.","authors":"Guihong Shi, Rui Tan, Yiyao Cao, Xiujue Zheng, Renya Zhan","doi":"10.1186/s12974-026-03843-x","DOIUrl":"https://doi.org/10.1186/s12974-026-03843-x","url":null,"abstract":"<p><p>Neuroinflammation has historically been viewed through a biochemical lens, governed by cytokines and danger signals. While this paradigm has provided foundational insights, integrating the physical dimension of tissue stiffening, hemodynamic shear stress, and compressive forces offers a more complete understanding of the pathological microenvironment of the central nervous system (CNS). In this Review, we examine Piezo1 as an important mechanosensitive channel that can translate such physical cues into neuroinflammatory responses. We synthesize emerging evidence showing that Piezo1-mediated calcium signaling can regulate activation, migration, and metabolic reprogramming in resident CNS cells and infiltrating immune populations. Importantly, the strength of evidence is not uniform across all cell types: genetic studies provide the strongest support in microglia, oligodendrocyte-lineage cells, and endothelial cells, whereas roles in astrocytes, dendritic cells, and T cells remain more context-dependent and emerging.Furthermore, we outline the distinct mechanical signatures across major CNS pathologies and discuss how Piezo1 may shape context-dependent outcomes-from plaque-associated microglial responses in Alzheimer's disease to mechanically restricted remyelination in multiple sclerosis, acute vascular or parenchymal injury in stroke and trauma, and emerging links to seizure-associated swelling and hyperexcitability in epilepsy. Finally, we propose an integrated \"Mechanical Alterations-Piezo1-Immune Regulation\" framework and discuss how mechano-therapeutic strategies might be used to modulate, rather than uniformly enhance or suppress, neuroinflammatory responses.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147816234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}