Journal of Neuroinflammation最新文献

{"title":"Genotype-driven sensitivity of mice to tick-borne encephalitis virus correlates with differential host responses in peripheral macrophages and brain.","authors":"Michaela Berankova, Jiri Holoubek, Vaclav Hönig, Zuzana Matusova, Martin Palus, Jiri Salat, Imtissal Krayem, Jarmila Vojtiskova, Pavel Svoboda, Veronika Pranclova, Lukas Valihrach, Peter Demant, Marie Lipoldova, Daniel Ruzek","doi":"10.1186/s12974-025-03354-1","DOIUrl":"10.1186/s12974-025-03354-1","url":null,"abstract":"<p><strong>Background: </strong>Tick-borne encephalitis (TBE) is the most common tick-borne viral infection in Eurasia. Outcomes range from asymptomatic infection to fatal encephalitis, with host genetics likely playing a role. BALB/c mice have intermediate susceptibility to TBE virus (TBEV) and STS mice are highly resistant, whereas the recombinant congenic strain CcS-11, which carries 12.5% of the STS genome on the BALB/c background, is more susceptible than BALB/c mice. In the present study, we employed these genetically distinct mouse models to investigate the host response to TBEV infection in both peripheral macrophages, one of the initial target cell populations, and the brain, the terminal target organ of the virus.</p><p><strong>Methods: </strong>TBEV growth and the production of key cytokines and chemokines were measured and compared in macrophages derived from BALB/c, CcS-11, and STS mice. In addition, brains from these TBEV-infected mouse strains underwent in-depth transcriptomic analysis.</p><p><strong>Results: </strong>Virus production in BALB/c and CcS-11 macrophages exhibited similar kinetics 24 and 48 h post-infection (hpi), but CcS-11 macrophages yielded significantly higher titers 72 hpi. Macrophages from both sensitive strains demonstrated elevated chemokine and proinflammatory cytokine production upon infection, whereas the resistant strain, STS, showed no cytokine/chemokine activation. Transcriptomic analysis of brain tissue demonstrated that the genetic background of the mouse strains dictated their transcriptional response to infection. The resistant strain exhibited a more robust cell-mediated immune response, whereas both sensitive strains showed a less effective cell-mediated response but increased cytokine signaling and signs of demyelination, with loss of oligodendrocytes.</p><p><strong>Conclusions: </strong>Our findings suggest that variations in susceptibility linked to host genetic background correspond with distinct host responses, both in the periphery upon virus entry into the organism and in the brain, the target organ of the virus. These results provide insights into the influence of host genetics on the clinical trajectory of TBE.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"22"},"PeriodicalIF":9.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059356","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":"NLRX1 limits inflammatory neurodegeneration in the anterior visual pathway.","authors":"Alexander J Gill, Matthew D Smith, Danny Galleguillos, Thomas Garton, Jackson W Mace, Sachin P Gadani, Swati Kumar, Aayush Pokharel, Krista Solem, Saahith Potluri, Omar Hussein, Giuliana Sardi Rogines, Arihant Singh, Annatje Clark, Peter A Calabresi, Marjan Gharagozloo","doi":"10.1186/s12974-025-03339-0","DOIUrl":"10.1186/s12974-025-03339-0","url":null,"abstract":"<p><p>Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). Using multiple experimental autoimmune encephalomyelitis (EAE) models, we discovered that NLRX1 protects neurons in the anterior visual pathway from inflammatory neurodegeneration. We quantified retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1^-/- and wild-type (WT) EAE mice and found increased RGC loss and axonal injury in Nlrx1^-/- mice compared to WT mice in both active immunization EAE and spontaneous opticospinal encephalomyelitis (OSE) models. To minimize the effects of Nlrx1^-/- on peripheral lymphocyte priming during EAE, we performed adoptive transfer experiments, in which activated myelin-specific T cells were transferred into lymphocyte-deficient Rag^-/- or Nlrx1^-/-Rag^-/- mice. In this model, we found more severe microgliosis and astrogliosis in the optic nerve of Nlrx1^-/-Rag^-/- mice compared to Rag^-/- mice, suggesting a regulatory role of NLRX1 in innate immune cells. Transcriptome analysis in primary astrocytes activated with LPS and IFNγ demonstrated that NLRX1 suppresses NF-κB activation and regulates mitochondrial oxidative phosphorylation in inflammatory reactive astrocytes. The novel pharmacologic NLRX1 activators NX-13 and LABP-66 decreased LPS-mediated gene expression of inflammatory cytokines and chemokines in mixed glial cultures. Moreover, treating EAE mice with oral LABP-66, compared to vehicle, after the onset of paralysis resulted in less anterior visual pathway neurodegeneration. These data suggest that pharmacologic NLRX1 activators have the potential to limit inflammatory neurodegeneration. This study highlights that NLRX1 could serve as a promising target for neuroprotection in progressive MS and other neurodegenerative diseases. Further studies are needed to better understand the cell-specific mechanisms underlying the neuroprotective role of NLRX1 in response to inflammation in the CNS.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"21"},"PeriodicalIF":9.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059359","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":"Characteristics of TSPO expression in marmoset EAE.","authors":"Irene Falk, Dragan Maric, Emily Leibovitch, Pascal Sati, Jennifer Lefeuvre, Nicholas J Luciano, Joseph Guy, Seung-Kwon Ha, David R Owen, Franklin Aigbirhio, Paul M Matthews, Daniel S Reich, Steven Jacobson","doi":"10.1186/s12974-025-03343-4","DOIUrl":"10.1186/s12974-025-03343-4","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and is a leading non-traumatic cause of disability in young adults. The 18 kDa Translocator Protein (TSPO) is a mitochondrial protein and positron emission tomography (PET)-imaging target that is highly expressed in MS brain lesions. It is used as an inflammatory biomarker and has been proposed as a therapeutic target. However, its specific pathological significance in humans is not well understood. Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a well-established primate model of MS. Studying TSPO expression in this model will enhance our understanding of its expression in MS. This study therefore characterizes patterns of TSPO expression in fixed CNS tissues from one non-EAE control marmoset and 8 EAE marmosets using multiplex immunofluorescence. In control CNS tissue, we find that TSPO is expressed in the leptomeninges, ependyma, and over two-thirds of Iba1 + microglia, but not astrocytes or neurons. In Iba1 + cells in both control and acute EAE tissue, we find that TSPO is co-expressed with markers of antigen presentation (CD74), early activation (MRP14), phagocytosis (CD163) and anti-inflammatory phenotype (Arg1); a high level of TSPO expression is not restricted to a particular microglial phenotype. While TSPO is expressed in over 88% of activated Iba1 + cells in acute lesions in marmoset EAE, it also is sometimes observed in subsets of astrocytes and neurons. Additionally, we find the percentage of Iba1 + cells expressing TSPO declines significantly in lesions > 5 months old and may be as low as 13% in chronic lesions. However, we also find increased astrocytic TSPO expression in chronic-appearing lesions with astrogliosis. Finally, we find expression of TSPO in a subset of neurons, most frequently GLS2 + glutamatergic neurons. The shift in TSPO expression from Iba + microglia/macrophages to astrocytes over time is similar to patterns suggested by earlier neuropathology studies in MS. Thus, marmoset EAE appears to be a clinically relevant model for the study of TSPO in immune dysregulation in human disease.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"19"},"PeriodicalIF":9.3,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052774","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":"Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus.","authors":"Bianca Caroline Bobotis, Mohammadparsa Khakpour, Olivia Braniff, Elisa Gonçalves de Andrade, Makenna Gargus, Micah Allen, Micaël Carrier, Joanie Baillargeon, Manu Rangachari, Marie-Ève Tremblay","doi":"10.1186/s12974-025-03341-6","DOIUrl":"10.1186/s12974-025-03341-6","url":null,"abstract":"<p><p>The brain presents various structural and functional sex differences, for which multiple factors are attributed: genetic, epigenetic, metabolic, and hormonal. While biological sex is determined by both sex chromosomes and sex hormones, little is known about how these two factors interact to establish this dimorphism. Sex differences in the brain also affect its resident immune cells, microglia, which actively survey the brain parenchyma and interact with sex hormones throughout life. However, microglial differences in density and distribution, morphology and ultrastructural patterns in physiological conditions during adulthood are largely unknown. Here, we investigated these aforementioned properties of microglia using the Four Core Genotypes (FCG) model, which allows for an independent assessment of gonadal hormones and sex chromosomal effects in four conditions: FCG XX and Tg XY^- (both ovaries); Tg XX^Sry and Tg XY^Sry (both testes). We also compared the FCG results with XX and XY wild-type (WT) mice. In adult mice, we focused our investigation on the ventral hippocampus across different layers: CA1 stratum radiatum (Rad) and CA1 stratum lacunosum-moleculare (LMol), as well as the dentate gyrus polymorphic layer (PoDG). Double immunostaining for Iba1 and TMEM119 revealed that microglial density is influenced by both sex chromosomes and sex hormones. We show in the Rad and LMol that microglia are denser in FCG XX compared to Tg XY^Sry mice, however, microglia were densest in WT XX mice. In the PoDG, ovarian animals had increased microglial density compared to testes animals. Additionally, microglial morphology was modulated by a complex interaction between hormones and chromosomes, affecting both their cellular soma and arborization across the hippocampal layers. Moreover, ultrastructural analysis showed that microglia in WT animals make overall more contacts with pre- and post-synaptic elements than in FCG animals. Lastly, microglial markers of cellular stress, including mitochondrion elongation, and dilation of the endoplasmic reticulum and Golgi apparatus, were mostly chromosomally driven. Overall, we characterized different aspects of microglial properties during normal physiological conditions that were found to be shaped by sex chromosomes and sex hormones, shading more light onto how sex differences affect the brain immunity at steady-state.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"18"},"PeriodicalIF":9.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143039491","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 NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis.","authors":"Xiaoyu Huang, Zhouao Zhang, Zhouyi Wang, Tiancheng Luo, Mingjin Yang, Xinyan Guo, Xue Du, Tianyu Ma, Yong Zhang","doi":"10.1186/s12974-025-03342-5","DOIUrl":"10.1186/s12974-025-03342-5","url":null,"abstract":"<p><strong>Background: </strong>B cell immune dysregulation plays a critical role in myasthenia gravis (MG). However, targeted B-cell therapy such as rituximab may result in long-term peripheral B cell clearance and allow for the survival of plasma cells, contributing to frequent infections and relapses. Therefore, we aimed to identify potential novel therapeutic targets that preserve part of B cell function while inhibiting antibody-secreting cells (ASCs).</p><p><strong>Methods: </strong>The transcriptome of sorted CD19⁺B cells obtained from MG patients in active and remission state was performed by RNA sequencing. The hallmark gene NF-kappaB-inducing kinase (NIK/MAP3K14) associated with NF-κB and TNF signaling was identified, and the expression levels of NIK in CD19⁺B cells, CD4⁺T cells and serum from new-onset MG patients and controls were validated by flow cytometry, qPCR and ELISA. In vitro and in vivo, the effects of NIK inhibitor (B022) on the function of CD19⁺B cells and CD4⁺T cells were detected under the MG PBMCs, sorted B cells and experimental autoimmune MG (EAMG) rat model, respectively.</p><p><strong>Results: </strong>The expression levels of NIK were upregulated in CD19⁺B cells, CD4⁺T cells and serum from new-onset MG patients. Notably, increased serum NIK levels were positively correlated with disease severity and decreased with disease remission. NIK inhibitor B022 significantly reduced B-cell activation, proliferation, ASCs differentiation and pathogenic function, as well as CD4⁺T cell activation and Th17 cells differentiation in vitro. Intraperitoneal injection of B022 ameliorated the severity of EAMG rats, and reduced proportion of pathogenic B and T cell subsets, antibody levels and postsynaptic membrane damage.</p><p><strong>Conclusions: </strong>Targeting NIK with small molecule kinase inhibitors can effectively shape B cell homeostasis, and exhibit protective effects in the EAMG rat model, which may be an effective novel treatment strategy for MG.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"17"},"PeriodicalIF":9.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143039494","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":"Single-cell RNA sequencing highlights the role of distinct natural killer subsets in sporadic amyotrophic lateral sclerosis.","authors":"Esther Álvarez-Sánchez, Álvaro Carbayo, Natalia Valle-Tamayo, Laia Muñoz, Joaquim Aumatell, Soraya Torres, Sara Rubio-Guerra, Jesús García-Castro, Judit Selma-González, Daniel Alcolea, Janina Turon-Sans, Alberto Lleó, Ignacio Illán-Gala, Juan Fortea, Ricard Rojas-García, Oriol Dols-Icardo","doi":"10.1186/s12974-025-03347-0","DOIUrl":"10.1186/s12974-025-03347-0","url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation and the infiltration of immune cells into the brain contribute to this process. However, no study has investigated the role of peripheral blood immune cells in ALS pathophysiology using single-cell RNA sequencing (scRNAseq).</p><p><strong>Methods: </strong>We aimed to characterize immune cells from blood and identify ALS-related immune alterations at single-cell resolution. For this purpose, peripheral blood mononuclear cells (PBMC) were isolated from 14 ALS patients and 14 cognitively unimpaired healthy individuals (HC), matched by age and gender, and cryopreserved until library preparation and scRNAseq. We analyzed differences in the proportions of PBMC, gene expression, and cell-cell communication patterns between ALS patients and HC, as well as their association with plasma neurofilament light (NfL) concentrations, a surrogate biomarker for neurodegeneration. Flow cytometry was used to validate alterations in cell type proportions.</p><p><strong>Results: </strong>We identified the expansion of CD56^dim natural killer (NK) cells in ALS (fold change = 2; adj. p-value = 0.0051), mainly driven by a specific subpopulation, NK_2 cells (fold change = 3.12; adj. p-value = 0.0001), which represent a mature and cytotoxic CD56^dim NK subset. Our results revealed extensive gene expression alterations in NK_2 cells, pointing towards the activation of immune response (adj. p-value = 9.2 × 10^- 11) and the regulation of lymphocyte proliferation (adj. p-value = 6.46 × 10^- 6). We also identified gene expression changes in other immune cells, such as classical monocytes, and distinct CD8 + effector memory T cells which suggested enhanced antigen presentation via major histocompatibility class-II (adj. p-value = 1.23 × 10^- 8) in ALS. The inference of cell-cell communication patterns demonstrated that the interaction between HLA-E and CD94:NKG2C from different lymphocytes to NK_2 cells is unique to ALS blood compared to HC. Finally, regression analysis revealed that the proportion of CD56^bright NK cells along with the ALSFRS-r, disease duration, and gender, explained up to 76.4% of the variance in plasma NfL levels.</p><p><strong>Conclusion: </strong>Our results reveal a signature of relevant changes occurring in peripheral blood immune cells in ALS and underscore alterations in the proportion, gene expression, and signaling patterns of a cytotoxic and terminally differentiated CD56^dim NK subpopulation (NK_2), as well as a possible role of CD56^bright NK cells in neurodegeneration.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"15"},"PeriodicalIF":9.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059361","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":"Cross-species comparisons between pigs and mice reveal conserved sex-specific intraspinal inflammatory responses after spinal cord injury.","authors":"Reena Kumari, Gabrielle V Hammers, Robert H Hammons, Andrew N Stewart, Steven M MacLean, Tracy Niedzielko, Lonnie E Schneider, Candace L Floyd, John C Gensel","doi":"10.1186/s12974-025-03338-1","DOIUrl":"10.1186/s12974-025-03338-1","url":null,"abstract":"<p><strong>Objective: </strong>Therapeutic translation is challenging in spinal cord injury (SCI) and large animal models with high clinical relevance may accelerate therapeutic development. Pigs have important anatomical and physiological similarities to humans. Intraspinal inflammation mediates SCI pathophysiology. The purpose of this study was to evaluate the effect of sex on inflammation and outcomes in a pig thoracic contusion/compression SCI model.</p><p><strong>Methods: </strong>Adult (gonad-intact) male and female Yucatan miniature swine were subjected to either SCI or sham (laminectomy-only) injury.</p><p><strong>Results: </strong>SCI caused locomotor dysfunction (measured with the Porcine Thoracic Injury Behavior Score) with some recovery over 6 weeks and limited tissue sparing at 6 weeks with no difference between sexes. Immunohistological evaluations of spinal cord tissue at 2 days and 6 weeks post-injury revealed intraspinal microglia/macrophage (IBA-1, CD68) and lymphocyte responses (T-cells (CD3) and B-cells (CD79a)) consistent with observations in rodents and humans. Astrocyte (GFAP) immunoreactivity was observed within the lesion core at 6 weeks in contrast to observations in rodents. No differences were seen for astrocytes, microglia, macrophages, B-cells, and neutrophil infiltration between males and females. Intraspinal CD3 + T-cell counts and T-cell microclusters were significantly higher in females compared to males 6 weeks post-injury. Interestingly, we observed a similar significant increase in intraspinal CD3 + T-cell accumulation in female vs. male mice at 6 weeks post-thoracic contusion SCI.</p><p><strong>Interpretation: </strong>Our observations indicate that sex is a potential biological variable for T-cell infiltration and may contribute to sex-based differences in SCI pathophysiology and recovery outcomes.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"16"},"PeriodicalIF":9.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028950","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":"TDP43 augments astrocyte inflammatory activity through mtDNA-cGAS-STING axis in NMOSD.","authors":"Zhuhe Liu, Yunmeng Bai, Bingtian Xu, Haixia Wen, Kechun Chen, Jingfang Lin, Yuanyuan Wang, Jiangping Xu, Haitao Wang, Fudong Shi, Jigang Wang, Honghao Wang","doi":"10.1186/s12974-025-03348-z","DOIUrl":"10.1186/s12974-025-03348-z","url":null,"abstract":"<p><p>Abnormality in transactivating response region DNA binding protein 43 (TDP43) is well-recognized as the pathological hallmark of neurodegenerative diseases. However, the role of TDP43 in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. Here, our observations demonstrate an upregulation of TDP43 in both in vitro and in vivo models of NMOSD, as well as in biological samples from NMOSD patients. Single-nucleus RNA sequencing revealed that NMOSD induced A1-like reactive astrocytes and astrocyte mitochondrial dysfunction in mice. We further found that NMOSD provoked the translocation of TDP43 to mitochondria and the release of mitochondrial DNA (mtDNA) into the cytoplasm. NMOSD caused activation of mtDNA/cyclic GMP-AMP synthase (cGAS) / stimulator of interferon genes (STING) pathway and A1-type inflammatory activation in astrocytes. Crucially, the knockdown of TDP43 markedly ameliorated NMOSD-induced mitochondrial dysfunction and the activation of the cGAS/STING pathway in astrocytes. Conversely, overexpression of TDP43 exacerbated these pathological changes. Specific silencing astrocytic TDP43 ameliorated NMOSD-induced injury in mice, and conversely, TDP43 overexpression intensified the injury. Meanwhile, both cGAS and STING inhibitors attenuated NMOSD-induced injury in mice. In summary, our data suggest that TDP43 exacerbates inflammatory activation of astrocytes in NMOSD through upregulating the mtDNA/cGAS/STING signaling pathway. Therefore, targeting TDP43 represents a compelling therapeutic strategy for NMOSD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"14"},"PeriodicalIF":9.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023733","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":"Therapeutic potential of targeting the IRF2/POSTN/Notch1 axis in nucleus pulposus cells for intervertebral disc degeneration.","authors":"Daxue Zhu, Zhaoheng Wang, Shijie Chen, Yanhu Li, Xuewen Kang","doi":"10.1186/s12974-025-03335-4","DOIUrl":"10.1186/s12974-025-03335-4","url":null,"abstract":"<p><strong>Background: </strong>Intervertebral disc degeneration (IDD) is a leading cause of low back pain, often linked to inflammation and pyroptosis in nucleus pulposus (NP) cells. The role of Periostin (POSTN) in IDD remains unclear.</p><p><strong>Objective: </strong>This study aims to investigate the influence of POSTN on pyroptosis and NLRP3 inflammasome activation in NP cells during IDD.</p><p><strong>Methods: </strong>IVD samples were collected from patients undergoing spinal surgery and classified according to the Pfirrmann grading system. Human NP cells were cultured and treated with IL-1β to induce a pyroptotic phenotype. Western blotting, Immunofluorescence (IF), and immunohistochemistry (IHC) assessed the expression levels of relevant proteins. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified the binding of IRF2 to the POSTN and GSDMD promoters and evaluated the activation levels of target genes. The severity of IDD was evaluated using MRI and histological analysis.</p><p><strong>Results: </strong>Deletion of POSTN significantly alleviated IDD by suppressing NLRP3 inflammasome activity and pyroptosis in NP cells. POSTN was found to aggravate NP cell pyroptosis by activating the NLRP3 inflammasome through the NF-κB (P65) and cGAS/STING signaling pathways. Furthermore, POSTN interacted with Notch1 to induce NLRP3 expression. IRF2 was identified as a regulator of POSTN at the transcriptional level, contributing to NLRP3 activation and NP cell pyroptosis. IRF2 also directly induced the transcriptional expression of GSDMD, mediating pyroptosis in NP cells. Chemical screening identified Glucosyringic acid (GA) as a direct inhibitor of POSTN, which delayed IDD progression.</p><p><strong>Conclusion: </strong>The study elucidates the pivotal role of POSTN in mediating NP cell pyroptosis through the NLRP3 inflammasome and highlights GA as a promising therapeutic candidate for IDD. These findings provide new insights into the molecular mechanisms of IDD and potential avenues for treatment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"13"},"PeriodicalIF":9.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023707","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 cold-inducible RNA-binding protein in CNS injury: molecular insights and therapeutic approaches.","authors":"Dmitriy Lapin, Archna Sharma, Ping Wang","doi":"10.1186/s12974-025-03340-7","DOIUrl":"10.1186/s12974-025-03340-7","url":null,"abstract":"<p><p>Central nervous system (CNS) injuries, such as ischemic stroke (IS), intracerebral hemorrhage (ICH) and traumatic brain injury (TBI), are a significant global burden. The complex pathophysiology of CNS injury is comprised of primary and secondary injury. Inflammatory secondary injury is incited by damage-associated molecular patterns (DAMPs) which signal a variety of resident CNS cells and infiltrating immune cells. Extracellular cold-inducible RNA-binding protein (eCIRP) is a DAMP which acts through multiple immune and non-immune cells to promote inflammation. Despite the well-established role of eCIRP in systemic and sterile inflammation, its role in CNS injury is less elucidated. Recent literature suggests that eCIRP is a pleiotropic inflammatory mediator in CNS injury. eCIRP is also being evaluated as a clinical biomarker to indicate prognosis in CNS injuries. This review provides a broad overview of CNS injury, with a focus on immune-mediated secondary injury and neuroinflammation. We then review what is known about eCIRP in CNS injury, and its known mechanisms in both CNS and non-CNS cells, identifying opportunities for further study. We also explore eCIRP's potential as a prognostic marker of CNS injury severity and outcome. Next, we provide an overview of eCIRP-targeting therapeutics and suggest strategies to develop these agents to ameliorate CNS injury. Finally, we emphasize exploring novel molecular mechanisms, aside from neuroinflammation, by which eCIRP acts as a critical mediator with significant potential as a therapeutic target and prognostic biomarker in CNS injury.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"12"},"PeriodicalIF":9.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007006","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}