Journal of Neuroinflammation最新文献

{"title":"N-Lactoyl-Phenylalanine modulates lipid metabolism in microglia/macrophage via the AMPK-PGC1α-PPARγ pathway to promote recovery in mice with spinal cord injury.","authors":"Weiyang Ying, Weidong Weng, Peifang Wang, Chi Pan, Jiani Qiu, Qianqian Huang, Gonghao Zhan, Xiaoli Chen","doi":"10.1186/s12974-025-03495-3","DOIUrl":"10.1186/s12974-025-03495-3","url":null,"abstract":"<p><p>The accumulation of lipids in microglia/macrophage-induced inflammation exacerbation represents a pivotal factor contributing to secondary injury following spinal cord injury (SCI). N-Lactoyl-Phenylalanine (L-P), a metabolic byproduct of exercise, exhibits the capacity to regulate carbohydrate and lipid metabolism and may serve as a potential regulator of lipid metabolism in microglia/macrophage. This study investigates the role of L-P in modulating lipid homeostasis in microglia/macrophage and its therapeutic implications for SCI recovery. By establishing a mouse model of SCI, we confirmed that L-P administration markedly altered lipid metabolism in microglia/macrophage. This metabolic reprogramming was mediated through the activation of the AMPK-PGC1α-PPARγ signaling pathway, which plays a crucial role in regulating cellular energy metabolism and inflammatory responses. Our findings demonstrate that L-P treatment enhances the lipid metabolic capacity of microglia/macrophage, thereby attenuating neuroinflammation and promoting tissue repair after injury. Moreover, the polarization of microglia/macrophage shifts toward the anti-inflammatory M2 phenotype, providing substantial support for the regenerative process of the injured spinal cord. Functional analysis revealed that mice treated with L-P exhibited significantly improved motor function compared to the control group. Collectively, these results underscore the therapeutic potential of L-P in SCI and suggest its utility as a metabolic intervention strategy by modulating microglia/macrophage lipid metabolism to accelerate recovery.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"167"},"PeriodicalIF":9.3,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512062","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":"Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading.","authors":"Xiaoli Liu, Huijin Wang, Xi Tian, Yingqi Luo, Minmin Ma, Zilong Zheng, Yaping Wang, Shi Feng, Qiushi Wang, Zhuo Xu, Wen Yao, Siqiang Ren","doi":"10.1186/s12974-025-03488-2","DOIUrl":"10.1186/s12974-025-03488-2","url":null,"abstract":"<p><p>Depression has been widely recognized as an important accelerating factor contributing to the aggravation of cognitive decline in Alzheimer's disease (AD) patients. Previous studies show that microglia-mediated neuroinflammation is a common and critical event in the etiology of both depression and dementia, but whether and how microglia participate in the process of depression-exacerbating AD pathology is largely unknown. By establishing the learned helplessness depression model on 5×FAD mice, we confirmed that depression can indeed promote Aβ plaque deposition and deteriorate the cognitive performance of the AD mice. Importantly, we found that microglial lactate concentration is dramatically increased in the depressed AD brain, leading to activation of potassium channel Kv1.3 likely through non-direct-lactylation. The activated Kv1.3 further facilitates Aβ-containing exosome spreading from microglia in the vicinity of Aβ plaque into the surrounding brain tissue. Notably, conditional knock-out of Kv1.3 in microglia can reverse the depression-induced acceleration of AD pathology and cognitive decline. Together, our study highlights an important function of microglia Kv1.3 in the promotion of Aβ propagation in the context of depression-exacerbating AD pathology.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"166"},"PeriodicalIF":9.3,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512061","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":"IFP35, a novel DAMP, aggravates neuroinflammation following acute ischemic stroke via TLR4/NF-κB/NLRP3 signaling.","authors":"Mengmeng Zhang, Bingnan Guo, Xiaowei Zhang, Dong Han, Lanxin Lv, Xiaoqing Yan, Chenglei Su, Dafei Chai, Ningjun Zhao, Xianliang Yan, Shuqun Hu","doi":"10.1186/s12974-025-03492-6","DOIUrl":"10.1186/s12974-025-03492-6","url":null,"abstract":"<p><strong>Background: </strong>Acute ischemic stroke is a disastrous disease characterized by damaging blood flow in the brain, leading to acute brain injury. Acute brain ischemia elicits severe inflammation, thus in turn, aggravates neural injury. Interferon-Induced Protein 35 (IFP35), is a 35 kDa protein, a novel type of DAMP that trigger inflammatory responses, exacerbating acute and chronic inflammatory disease. This study aimed to investigate the potential neuroinflammation role of IFP35 in acute ischemic stroke in a mouse model of MCAO.</p><p><strong>Methods: </strong>C57BL/6 male mice were subjected to middle cerebral artery occlusion (MCAO) to establish an animal model of acute ischemic stroke. Leveraging serum from stroke patients, serum and brain tissue after MCAO mice, IFP35 was released. Immunofluorescence assay was used to investigated the cell sources of IFP35 expression after MCAO. The impact of IFP35 on neuroinflammation and neural injury was assessed by siRNA-mediated cerebral IFP35 knockdown. Behavioral tests, and brain tissues were harvested for histological analysis and biochemical assays. TUNEL assays were used to evaluate neuronal damage. TTC staining was performed to assess infarction volumes. Additionally, using western blotting and immunofluorescence assays, we further assessed the contribution of TLR4/NF-κB/NLRP3 signaling in MCAO mice and BV2 cells.</p><p><strong>Results: </strong>IFP35 was accumulated in peripheral blood of cerebral ischaemia patients, ischemia mice serum, as well as peri-infarct regions in focal cerebral ischemia mice. Although endothelial cells, microglia, and astrocytes are capable of expressing IFP35, cerebral neural cells seem to express and release more IFP35 compare to other cell types. Knockdown of IFP35 alleviated the production of neuroinflammatory cytokines, decreased neuronal death, and minimized infarct volumes, ultimately leading to improved neurological outcomes. Importantly, IFP35 triggered the activation of NF-κΒ and NLRP3 signaling, exacerbating neuroinflammation and brain injury by binding its receptor TLR4.</p><p><strong>Conclusions: </strong>This study revealed IFP35 as a novel DAMP released during cerebral ischemia that promotes neuroinflammation and injury, expanding the current understanding of inflammatory networks following stroke.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"164"},"PeriodicalIF":9.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497345","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":"Group 2 innate lymphoid cells drive inhibitory synapse formation with lasting effects on learning and memory.","authors":"Johannes Steffen, Divija Deshpande, Henning Peter Düsedau, Janna Schmitz, Caio Andreeta Figueiredo, Laura Velleman, Claudia Pitzer, Christoph S N Klose, Ildiko R Dunay","doi":"10.1186/s12974-025-03485-5","DOIUrl":"10.1186/s12974-025-03485-5","url":null,"abstract":"<p><p>The immune system provides multiple layers of protection that extend beyond conventional pathogen defense, including context-dependent modulation of behavior. However, the mechanisms driving these immune-mediated behavioral modifications remain incompletely understood. Here, we demonstrate that group 2 innate lymphoid cells (ILC2s) shape hippocampal synaptic development during early postnatal stages, with lasting effects on adult behavior, learning, and memory.Using flow synaptometry, we identified a selective reduction in hippocampal VGAT⁺ GABAergic/glycinergic inhibitory synapse frequency at postnatal day 15 in ILC2-deficient mice, while the proportions of inhibitory GABAergic (NL2⁺) or excitatory glutamatergic (GluR1⁺) synapses remained unaltered. These synaptic changes occurred without detectable phenotypical changes in cortical and hippocampal microglia. In adulthood, ILC2-deficient mice displayed significant impairments in hippocampus-dependent tasks, such as active place avoidance and operant conditioning, reflecting deficits in learning and memory.Our findings reveal a critical role for ILC2s in the formation of inhibitory synapses in the hippocampus, highlighting the impact of immune signaling on neuronal network maturation during a crucial period of brain development. This early immune-mediated modulation may have lasting effects on neuronal circuitry and cognitive functions that persist into adulthood, emphasizing the long-term implications of neuro-immune interactions for normal cognitive development and function.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"163"},"PeriodicalIF":9.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the RAGE-RIPK1 binding site attenuates diabetes-associated cognitive deficits.","authors":"Lin Gao, Shidi Wu, Bin Hu, Qiuyu Zhang, Yifei Wu, Hui Li, Ye Qian, Chengyu Huang, Xiangru Wen, Hui Li, Aifang Cheng, Yuanjian Song, Changjiang Ying, Xiaoyan Zhou","doi":"10.1186/s12974-025-03489-1","DOIUrl":"10.1186/s12974-025-03489-1","url":null,"abstract":"<p><p>Microglial activation can cause neuroinflammation and the consequent neurological impairments play prominent roles in diabetes-associated cognitive deficits. Receptor-interacting protein kinase 1 (RIPK1) phosphorylation is involved in this deleterious microglial activation, but the exact molecular mechanisms are not clear. Here, RIPK1 expression was increased in diabetic patients with cognitive impairment. Furthermore, in diabetic mice, RIPK1 death domain directly binds to C-terminal of the receptor for advanced glycation end products (ctRAGE) could regulate RIPK1 phosphorylation in microglia. This RAGE-RIPK1 complex activates inflammatory signaling, resulting in cascades that ultimately promote cognitive impairment in diabetic mice. An engineered brain-targeting RIPK1 peptide blocked binding of RIPK1 to RAGE, which inhibited RIPK1 phosphorylation, decreased neuroinflammation, improved neuronal morphology and function, and prevented diabetes-associated cognitive deficits in mice. This study uncovers a previously unknown mechanism of neuroinflammation and suggests a novel therapeutic avenue for treating cognitive deficits induced by hyperglycemia.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"162"},"PeriodicalIF":9.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340216","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":"Pro-repair macrophages driven by CGRP rescue white matter integrity following intracerebral hemorrhage.","authors":"Huaping Huang, Yirui Kuang, Yang Chen, Yi Zhang, Jiayin Zhou, Xian Yu, Yonghe Zheng, Lingxin Cai, Wanglu Hu, Liansheng Gao, Haijian Wu, Hui Ling, Xiao Dong, Hang Zhou, Xiaobo Yu, Yucong Peng, Gao Chen, Xiaoyu Wang, Wei Yan","doi":"10.1186/s12974-025-03483-7","DOIUrl":"10.1186/s12974-025-03483-7","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"161"},"PeriodicalIF":9.3,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340215","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":"KChIP3 fosters neuroinflammation and synaptic dysfunction in the 5XFAD mouse model of Alzheimer's disease.","authors":"Bolivar Arcos-Encarnación, Eladio Cortes-Flores, Isabel Barón-Mendoza, Jorge Luis Almazán, David Valle-García, Sol Díaz de León-Guerrero, Ladislav Hovan, Karla F Meza-Sosa, Nohemi Camacho-Concha, Jeovanis Gil, Marieke Lydia Kuijjer, Aliesha González-Arenas, Sergio Encarnación-Guevara, Gustavo Pedraza-Alva, Leonor Pérez-Martínez","doi":"10.1186/s12974-025-03426-2","DOIUrl":"10.1186/s12974-025-03426-2","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by β-amyloid (βA) accumulation, neuroinflammation, excessive synaptic pruning, and cognitive decline. Despite extensive research, effective treatments remain elusive. Here, we identify potassium channel-interacting protein 3 (KChIP3) as a key driver of AD pathology using the 5XFAD mouse model. KChIP3 levels were significantly elevated in the hippocampus of 5XFAD mice, correlating with βA burden and neuroinflammation. This upregulation was triggered by inflammatory signaling via the NLRP3 inflammasome and Caspase-1 activation. Notably, genetic deletion of KChIP3 (5XFAD/KChIP3^-/-) markedly reduced βA plaque deposition, pro-inflammatory cytokines, reactive gliosis, and expression of inflammation-related proteins (APO, CLU, MDK). Transcriptomic and proteomic analyses revealed restored synaptic markers (CD47, CD200, CACNB4, GDA) and a shift of the disease-associated microglial (DAM-1) phenotype. Mechanistically, we propose that KChIP3 amplifies AD pathology through two key mechanisms: (1) sustaining neuroinflammation by upregulating pro-inflammatory genes and (2) impairing synaptic integrity by repressing genes critical for neuronal function. Consistently, KChIP3 deletion enhanced dendritic complexity, synaptic plasticity, and cognitive performance in 5XFAD mice. These findings position KChIP3 as a potential therapeutic target for mitigating neuroinflammation and synaptic dysfunction in AD and highlight its potential as a biomarker for disease progression.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"160"},"PeriodicalIF":9.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333326","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 glial fibrillary acidic protein in glaucoma: a monoclonal antibody approach to modulate glial reactivity and neuroinflammation for neuroprotection.","authors":"Chaoqiang Guan, Linglin Zhang, Kristian Nzogang Fomo, Jie Yang, Norbert Pfeiffer, Franz H Grus","doi":"10.1186/s12974-025-03482-8","DOIUrl":"10.1186/s12974-025-03482-8","url":null,"abstract":"<p><strong>Background: </strong>Glaucoma is a progressive neurodegenerative disorder that leads to irreversible vision loss, with neuroinflammation recognized as a key factor. Overexpression of glial fibrillary acidic protein (GFAP) is linked to glaucoma pathogenesis and plays a pivotal role in astrocyte-driven neuroinflammation. This study aimed to assess the neuroprotective effects of a monoclonal antibody (mAb) targeting GFAP in glaucoma and to elucidate the underlying mechanisms.</p><p><strong>Methods: </strong>An ocular hypertension (OHT) glaucoma model was established in female Sprague Dawley rats using episcleral vein occlusion. Three doses of GFAP mAb (2.5, 25, 50 µg) or vehicle were administered via intravitreal injection. Retinal nerve fiber layer (RNFL) thickness and photopic electroretinogram were monitored longitudinally. Retinal ganglion cell (RGC) survival and glial responses were evaluated with immunostaining. Western blot and microarray analyses were performed to investigate molecular and pathway alterations. Additionally, a cobalt chloride (CoCl₂)-induced degenerative R28 cell model was used to validate the protective effects of GFAP mAb in vitro. A bioinformatics re-analysis of a public glaucomatous retina protein dataset was conducted using GSEA, GO, and Cytoscape with GENEMANIA.</p><p><strong>Results: </strong>OHT resulted in a significant loss of RNFL thickness, PhNR amplitude, and RGC survival, all of which were preserved by GFAP mAb treatment. Retinal astrocyte reactivity was inhibited by GFAPmAb in a dose-dependent manner by suppressing GFAP protein overexpression. Notably, 25 µg GFAP mAb effectively regulated both astrocyte and microglial reactivity, leading to a substantial attenuation of neuroinflammation. Mechanistically, GFAP mAb inhibited the p38 MAPK and NF-κB pathways and the NLRP3/Caspase-1/GSDMD axis. In vitro, GFAP mAb improved R28 cell viability under CoCl₂ exposure while reducing cell death via inhibition of pyroptosis. Bioinformatic re-analysis highlighted gliosis as a prominent pathway in the glaucomatous retina and indicated GFAP and Caspase1 as central nodes in the putative mechanism network modulated by GFAP mAb.</p><p><strong>Conclusions: </strong>This study demonstrates that GFAP mAb inhibits astrogliosis and glial-glial activation, exerting neuroprotection through the inhibition of inflammation and pyroptosis. The findings suggest that targeting GFAP represents a promising immunotherapeutic strategy for glaucoma treatment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"159"},"PeriodicalIF":9.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317139","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":"Hypothalamic kisspeptin alleviates myasthenia gravis by regulating Th1/Th17/Treg balance through Inhibition of NF-κB signaling pathway.","authors":"Dan Lu, Linqi Liu, Wenjun Que, Rui Fan, Pingyang Ke, Jing Dong, Yaoqi Gan, Fei Xiao","doi":"10.1186/s12974-025-03486-4","DOIUrl":"10.1186/s12974-025-03486-4","url":null,"abstract":"<p><strong>Background: </strong>Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular junctions. While neuroendocrine-immune system dysfunction plays a crucial role in the development of autoimmune diseases, its involvement in MG remains largely unexplored. Kisspeptin, a neuropeptide hormone and endogenous ligand for GPR54 receptor, has been demonstrated to regulate antitumor immunity, antiviral immunity, and several autoimmune diseases. However, the role and mechanism of kisspeptin in MG remain to be elucidated.</p><p><strong>Methods: </strong>Serum kisspeptin levels were measured by ELISA in MG patients and experimental autoimmune myasthenia gravis (EAMG) rats. EAMG rats were treated with KP10 (kisspeptin analog) to evaluate its effects on body weight, clinical scores, grip strength, antibody levels, and complement deposition. Hypothalamic Kiss1 expression was assessed using Western blot and immunofluorescence. Stereotactic injection of adeno-associated virus overexpressing Kiss1 was performed to study its regulatory effects on disease progression. CD4⁺ T cell transfer via tail vein, Western blot, and flow cytometry were employed to investigate KP10's modulatory effects on CD4⁺ T cell subsets and the NF-κB signaling pathway.</p><p><strong>Results: </strong>Kisspeptin expression was significantly decreased in both MG patient sera and EAMG rat sera, with reduced hypothalamic Kiss1 expression in EAMG rats. Either hypothalamic Kiss1 overexpression or intraperitoneal KP10 administration significantly improved clinical signs in EAMG rats. Further in vivo and in vitro studies revealed that KP10 ameliorated EAMG clinical signs by modulating Th1/Th17/Treg cell balance through inhibition of NF-κB signaling pathway activation in CD4⁺ T cells.</p><p><strong>Conclusion: </strong>This study elucidates that Kisspeptin secreted by hypothalamic participates in MG pathogenesis through the Kisspeptin-GPR54-NF-κB signaling axis by regulating CD4⁺ T cell subset balance, suggesting that the kisspeptin/GPR54 pathway may serve as a potential therapeutic target for MG treatment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"158"},"PeriodicalIF":9.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310059","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":"Changes in metabolite profiles in the cerebrospinal fluid and in human neuronal cells upon tick-borne encephalitis virus infection.","authors":"Satoshi Suyama, Sally Boxall, Benjamin Grace, Andrea Fořtová, Martina Pychova, Lenka Krbkova, Rupasri Mandal, David Wishart, Diane E Griffin, Daniel Růžek, Niluka Goonawardane","doi":"10.1186/s12974-025-03478-4","DOIUrl":"10.1186/s12974-025-03478-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Tick-borne encephalitis virus (TBEV) is a significant threat to human health. The virus causes potentially fatal disease of the central nervous system (CNS), for which no treatments are available. TBEV infected individuals display a wide spectrum of neuronal disease, the determinants of which are undefined. Changes to host metabolism and virus-induced immunity have been postulated to contribute to the neuronal damage observed in infected individuals. In this study, we evaluated the cytokine, chemokine, and metabolic alterations in the cerebrospinal fluid (CSF) of symptomatic patients infected with TBEV presenting with meningitis or encephalitis. Our aim was to investigate the host immune and metabolic responses associated with specific TBEV infectious outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;CSF samples of patients with meningitis (n = 27) or encephalitis (n = 25) were obtained upon consent from individuals hospitalised with confirmed TBEV infection in Brno. CSF from uninfected control patients was also collected for comparison (n = 12). A multiplex bead-based system was used to measure the levels of pro-inflammatory cytokines and chemokines. Untargeted metabolomics followed by bioinformatics and integrative omics were used to profile the levels of metabolites in the CSF. Human motor neurons (hMNs) were differentiated from induced pluripotent stem cells (iPSCs) and infected with the highly pathogenic TBEV-Hypr strain to profile the role(s) of identified metabolites during the virus lifecycle. Virus infection was quantified via plaque assay.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Significant differences in proinflammatory cytokines (IFN-α2, TSLP, IL-1α, IL-1β, GM-CSF, IL-12p40, IL-15, and IL-18) and chemokines (IL-8, CCL20, and CXCL11) were detected between neurological-TBEV and control patients. A total of 32 CSF metabolites differed in TBE patients with meningitis and encephalitis. CSF S-Adenosylmethionine (SAM), Fructose 1,6-bisphosphate (FBP1) and Phosphoenolpyruvic acid (PEP) levels were 2.4-fold (range ≥ 2.3-≥3.2) higher in encephalitis patients compared to the meningitis group. CSF urocanic acid levels were significantly lower in patients with encephalitis compared to those with meningitis (p = 0.012209). Follow-up analyses showed fluctuations in the levels of O-phosphoethanolamine, succinic acid, and L-proline in the encephalitis group, and pyruvic acid in the meningitis group. TBEV-infection of hMNs increased the production of SAM, FBP1 and PEP in a time-dependent manner. Depletion of the metabolites with characterised pharmacological inhibitors led to a concentration-dependent attenuation of virus growth, validating the identified changes as key mediators of TBEV infection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our findings reveal that the neurological disease outcome of TBEV infection is associated with specific and dynamic metabolic signatures in the cerebrospinal fluid. We describe a new in vitro model for in-d","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"157"},"PeriodicalIF":9.3,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293948","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}