Journal of Neuroinflammation最新文献

{"title":"Pharmacological inhibition of the cGAS-STING pathway suppresses microglia pyroptosis in sepsis-associated encephalopathy.","authors":"Qing-Quan Zeng, Yang Qi, Hui Yu, Ying Xu, Jin-Xing Chen, You-Wei Zheng, Gui-Fei Zhang, Qiao-Ling Zhang, Yan-Hua Zheng, Jing Guo, Zi-Hong Zhao, Fa-Sheng Wang, Gui-Lin Jin","doi":"10.1186/s12974-025-03507-2","DOIUrl":"10.1186/s12974-025-03507-2","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"176"},"PeriodicalIF":9.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600743","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":"Liver-specific expression of ANGPTL8 promotes Alzheimer's disease progression through activating microglial pyroptosis.","authors":"Jiarui Wei, Lin Hu, Shufan Xu, Fan Yang, Fusheng Liao, Ying Tang, Xin Shen, Xiaoqiao Zhang, Xinggang Fang, Yifan Li, Li Ding, Zhuo Chen, Shanchun Su, Junhua Cheng, Yong Huang, Qian Chen, Daqing Ma, Qiufang Zhang, Xingrong Guo","doi":"10.1186/s12974-025-03487-3","DOIUrl":"10.1186/s12974-025-03487-3","url":null,"abstract":"<p><strong>Introduction: </strong>Liver dysfunction contributes to Alzheimer's disease (AD) pathogenesis, and evidence suggests that the liver is involved in amyloid β (Aβ) clearance, and regulates Aβ deposition in the brain. However, the specific regulatory mechanism remains elusive.</p><p><strong>Objectives: </strong>Angiopoietin-like protein 8 (ANGPTL8), a high expression of liver-specific secreted proinflammatory factor, crosses the blood‒brain barrier from the bloodstream to abnormally activate microglia and promote AD progression.</p><p><strong>Methods: </strong>The ANGPTL8^-/- mice and 5 × FAD mice were crossed mutated and subjected to the Morris water maze test and novel object recognition test to assess cognitive ability in different cohorts. Thioflavin-S, NeuN, and Nissl staining were used to assess Aβ deposition and neuron loss. The number of phagocytic microglia was evaluated with Fitc latex beads. Adeno-associated virus 8 (AAV8) hydrodynamically injected restored the liver ANGPTL8 levels of ANGPTL8^-/- 5 × FAD mice for further experiments. Single-cell RNA sequencing, bulk RNA sequencing and transmission electron microscopy were used to explore the role of ANGPTL8 in regulating AD progression, and drug screening was carried out to identify an effective inhibitor of ANGPTL8.</p><p><strong>Results: </strong>ANGPTL8 knockout improved cognitive function and reduced Aβ deposition by reducing microgliosis and microglial activation in 5xFAD mice. Mechanistically, ANGPTL8 crossed the blood‒brain barrier and interacted with the microglial membrane receptor PirB/LILRB2. This interaction subsequently activated the downstream NLRP3 inflammasome, leading to microglial pyroptosis and exacerbating the Aβ-induced release of inflammatory factors, thereby accelerating AD progression. Furthermore, the administration of metformin, an ANGPTL8 inhibitor, improved learning and memory deficits in 5 × FAD mice by negating microglial pyroptosis and neuroinflammation.</p><p><strong>Conclusions: </strong>ANGPTL8 aggravates microglial pyroptosis via the PirB/NLRP3 pathway to accelerate the pathogenesis of AD. Targeting high expression of ANGPTL8 in the liver may hold potential for developing therapies for AD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"177"},"PeriodicalIF":9.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600742","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":"MAVS signaling of long-lived brain-resident myeloid cells is needed during viral encephalitis to adjust the transcriptome of CNS infiltrating CD8⁺ T cells.","authors":"Andreas Pavlou, Luca Ghita, Felix Mulenge, Inken Waltl, Olivia Luise Gern, Pia-Katharina Larsen, Bibiana Costa, Veronica Duran, Lena Mareike Busker, Shelly J Robertson, Yvonne Lueder, Stephan Halle, Reinhold Förster, Sonja M Best, Martin Stangel, Ulrich Kalinke","doi":"10.1186/s12974-025-03497-1","DOIUrl":"10.1186/s12974-025-03497-1","url":null,"abstract":"<p><p>Neurotropic viruses like vesicular stomatitis virus (VSV) can infect the central nervous system (CNS) through the olfactory route. Following intranasal instillation, VSV moves along the axons of olfactory sensory neurons to the olfactory bulb. While within the olfactory bulb the spread of the virus is controlled by microglia activation and the recruitment of peripheral leukocytes, some of the underlying mechanisms remain unknown. To investigate these mechanisms, we used mice with conditional deletions of the mitochondrial antiviral-signaling protein (MAVS), an adaptor for RIG-I-like receptor (RLR) signaling. By selectively deleting MAVS in neurons, astrocytes, or long-lived myeloid cells, we discovered that RLR signaling specifically within brain-resident myeloid cells is crucial for protection against the virus. Infected mice with a MAVS deletion in these myeloid cells showed normal myeloid cell and leukocyte infiltration into the brain. However, the P2RY12⁺ microglia showed aberrant expression of genes involved in antigen cross-presentation. Furthermore, flow cytometry experiments revealed diminished MHC class I expression on MAVS deficient microglia. Moreover, CNS infiltrating CD8⁺ T cells had dysfunctional transcriptional profiles. Therefore, our findings indicate that during viral CNS infection, MAVS signaling in brain-resident myeloid cells, presumably microglia, is essential for antigen cross-presentation and the relicensing of protective, infiltrating CD8⁺ T cells.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"175"},"PeriodicalIF":9.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575693","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":"LAG3 limits regulatory T cell proliferation in α-synuclein gut-to-brain transmission model.","authors":"Wei-Xin Kong, Zhi-Ling Zhang, Jin Li, Si Zhu, Chong Li, Xiao-Li Dong, Ting-Ting Gan, Di Hu, Feng-Chu Liang, Ping-Yi Xu, Wen-Yuan Guo","doi":"10.1186/s12974-025-03502-7","DOIUrl":"10.1186/s12974-025-03502-7","url":null,"abstract":"<p><strong>Background: </strong>Pathological α-synuclein (α-syn) can spread from the gut to the central nervous system (CNS), with CD4 + T cells playing a key role in this process. Lymphocyte activation gene 3 (LAG3) is involved in intestinal inflammation, regulates CD4 + T cell proliferation and function, and can specifically bind to pathological α-syn during cell-to-cell transmission. However, it remains unclear whether LAG3 is involved in the spread of pathological α-syn from the gut to the brain.</p><p><strong>Methods: </strong>We utilized LAG3 knockout mice, combined with injection of α-syn preformed fibril (PFF) into the longitudinal and intermediate muscle layers of the pylorus and duodenum to model Parkinson's disease (PD). We used Immunohistochemistry staining, Western Blot, Flow cytometry to detect the changes of TH, α-syn, pro-inflammatory factors, barrier-related proteins and CD4 + T cells differentiation.</p><p><strong>Results: </strong>Our results show that LAG3 knockout partially alleviates psychological and behavioral deficits, dopamine system damage, and the gut-to-brain transmission of α-syn, which correlates with enhanced regulatory T cell (Treg) cell proliferation. Furthermore, LAG3 knockout improved intestinal dysfunction and increased the expression of tight junction proteins in both the gut and the blood-brain barrier (BBB). In CD4 + T cells isolated from the spleen, LAG3 knockout suppressed the aggregation of α-syn PFF, thereby inhibiting the toxic T-cell response induced by α-syn PFF. LAG3 deficiency also enhanced the IL-2/STAT5 signaling pathway, which regulates Treg proportions both in vivo and in vitro.</p><p><strong>Conclusions: </strong>Our findings demonstrated that LAG3 intrinsically limits Treg cell proliferation and function in the environment with pathological α-syn and promotes the gut-to-brain transmission of α-syn.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"174"},"PeriodicalIF":9.3,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567491","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":"Factor-H-related protein 1 (FHR1), a promotor of para-inflammation in age-related macular degeneration.","authors":"Andjela Sekulic, Sarah M Herr, Kelly Mulfaul, Inga-Marie Pompös, Silvia Winkler, Carola Dietrich, Benedikt Obermayer, Robert F Mullins, Thomas Conrad, Peter F Zipfel, Florian Sennlaub, Christine Skerka, Olaf Strauß","doi":"10.1186/s12974-025-03499-z","DOIUrl":"10.1186/s12974-025-03499-z","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD), a multifactorial type of retinal degeneration represents the most common cause for blindness in elderly. Polymorphisms in complement factor-H increase, while absence of factor-H-related protein-1 (FHR1) decreases the AMD risk, currently explained by their opposing relationship. Here we identify a FHR1-driven pathway fostering chronic cellular inflammation. FHR1 accumulates below the retinal pigment epithelium (RPE) in AMD donor tissue and similarly the murine homolog, muFHR1 is abundant in three AMD-relevant mouse models. These mouse models express the muFHR1 receptor EGF-like module-containing mucin-like hormone receptor 1 (Emr1) on the RPE and on invading mononuclear phagocytes (MP), where both cells form clusters via muFHR1/Emr1. FHR1 ignited EMR2-dependent Ca²⁺-signals and gene expression in both human RPE cell line and in vivo where muFHR1 affects Emr1⁺ cells (RPE and MP) gene expression shown by RNAseq analysis. As muFHR1 deletion in mice revealed significantly reduced MP invasion and neoangiogenesis in laser-induced choroidal neovascularization, we hypothesize that FHR1 accumulates, stabilizes and activates MP in the stage of RPE degeneration.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"173"},"PeriodicalIF":9.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560430","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 sensory neurons as regulators of neuro-immune-microbial interactions: from molecular mechanisms to precision therapy for IBD/IBS.","authors":"Ning Sun, Li-Shuang Cao, Wan-Yu Xia, Jun-Meng Wang, Qiao-Feng Wu","doi":"10.1186/s12974-025-03500-9","DOIUrl":"10.1186/s12974-025-03500-9","url":null,"abstract":"<p><p>As potentially important biosensors within the intestinal mucosal barrier, gut sensory neurons appear to dynamically orchestrate tissue homeostasis through multimodal integration of mechanical forces, chemical cues, and microbial metabolites. While current research indicates gut sensory neurons may play a significant role in the pathophysiology of IBD/IBS, the precise etiological mechanisms underlying these disorders require further investigation. In the enteric nervous system, intrinsic primary afferent neurons (IPANs) show distinct molecular characteristics compared to peripheral sensory neurons originating from the dorsal root ganglia (DRG) and vagal ganglia (NG/JG, nodose/jugular ganglia). These neuronal subtypes appear to orchestrate bidirectional epithelial-immune communication through context-dependent release of neurochemical signals, potentially establishing a dynamic neuromodulatory network. This comprehensive review will examine the latest findings on the relationship between these sensory neurons and intestinal diseases, and explore an integrated therapeutic framework based on a triple synergistic strategy. This framework could encompass precise molecular-level modulation through targeting neurotransmitters and their receptors, systemic-level neural regulation utilizing electrical nerve stimulation techniques, and ecological reprogramming mediated by gut microbiota. This potential approach may provide a possible translational pathway from mechanistic exploration to practical application, with implications for personalized clinical interventions for IBD/IBS.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"172"},"PeriodicalIF":9.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553789","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":"EphB2-mediated ephrin-B reverse signaling on microglia drives an anti-viral, but inflammatory and neurotoxic response associated with HIV.","authors":"Jeffrey Koury, Hina Singh, Samantha N Sutley-Koury, Dominic Fok, Xinru Qiu, Ricky Maung, Benjamin B Gelman, Iryna M Ethell, Marcus Kaul","doi":"10.1186/s12974-025-03481-9","DOIUrl":"10.1186/s12974-025-03481-9","url":null,"abstract":"<p><strong>Background: </strong>Pathological inflammation with a loss of synaptic integrity and function has been implicated in HIV Associated Neurocognitive Disorders (HAND). Although therapeutics exist to increase the lifespan of people living with HIV (PLWH), they are not effective at preventing neuroinflammation and HIV induced neuronal damage persists. In this study, we investigate the ephrin-B/EphB axis, which regulates inflammation, in post-mortem brain specimen of PLWH and experimental models in order to assess its potential role in HIV induced neuroinflammation.</p><p><strong>Methods: </strong>We analyze mRNA samples of post-mortem brain specimen of PLWH and uninfected controls obtained from the National NeuroAIDS Tissue Consortium (NNTC) and, for comparison, of a transgenic mouse model of neuroHIV using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Follow-up experiments employ mouse brain tissue and in vitro models, including immortalized human microglia, human induced pluripotent stem cell (iPSC)-derived mixed neuroglial cell cultures, cellular and molecular interference, functional and multiplex assays, immunofluorescence and mRNA sequencing to examine the role of the ephrin-B/EphB axis in neuroinflammation and the associated neurotoxicity.</p><p><strong>Results: </strong>Using qRT-PCR we find increased expression of EphB2 in post-mortem brain of PLWH, and detect a correlation with pro-viral DNA, viral RNA and an inverse correlation with abstract executive function and verbal fluency. Increased expression of ephrin-B/EphB at mRNA and protein level is also observed in brains of a transgenic mouse model of neuroHIV suggesting the upregulation can be driven, at least in part, by expression of viral gp120 envelope protein and a type I interferon, IFNβ. Additionally, we find induction of ephrin-B1 expression in microglia following activation by IFNβ. Given the previously reported impact of EphB2 on inflammation in the periphery, the functional role of EphB2-mediated ephrin-B reverse signaling on microglia is assessed for a pro-inflammatory and anti-viral signature. We find that EphB2 treated microglia secrete inflammatory and anti-viral factors but also exert contact-independent neurotoxicity. Finally, knockdown of microglial ephrin-B1, an EphB2 binding partner, shows a partial alleviation of the microglial pro-inflammatory signature and neurotoxicity.</p><p><strong>Conclusion: </strong>Our study suggests that elevated EphB2, and its reverse signaling through ephrin-B1 in microglia contribute to neuroinflammation and neurotoxicity in neuroHIV.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"171"},"PeriodicalIF":9.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12211399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528360","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":"Exercise-induced irisin ameliorates cognitive impairment following chronic cerebral hypoperfusion by suppressing neuroinflammation and hippocampal neuronal apoptosis.","authors":"Weiping Xiao, Yibing Yang, Lu Bai, Peixuan Yang, Runze Li, Daizhi Yang, Fanying Li, Lingzhi Quan, Qiupeng Liang, Yan Yan, Tiewei Qi, Feng Liang","doi":"10.1186/s12974-025-03493-5","DOIUrl":"10.1186/s12974-025-03493-5","url":null,"abstract":"<p><strong>Background: </strong>Chronic cerebral hypoperfusion (CCH) is a pathophysiological hallmark of vascular dementia, the second most common form of dementia. CCH exerts complex and subtle detrimental effects on both the brain and peripheral systems. Irisin is a polypeptide primarily expressed in contracting skeletal muscle and the brain. However, its role in CCH remains unclear. This study aimed to investigate the effects of CCH on irisin metabolism and whether increasing endogenous irisin levels through forced aerobic exercise (FAE) could confer neuroprotection against secondary brain injury induced by CCH.</p><p><strong>Methods: </strong>A total of 212 adult (8-week-old) male C57BL/6 mice were randomly assigned to either sham or CCH groups. CCH was induced by bilateral common carotid artery stenosis. FAE consisted of daily swimming (1 h/day, 5 days/week, for 5 weeks). Two subgroups of CCH mice received daily intraperitoneal injections of either DMSO or cilengitide trifluoroacetate (CT), a selective inhibitor of integrin αV and β5 (the irisin receptor), during FAE. ELISA and western blotting were used to assess irisin expression, while western blotting, TUNEL, immunofluorescence staining, and neurobehavioral tests were conducted to evaluate neurofunctional outcomes.</p><p><strong>Results: </strong>Hippocampal and serum irisin levels were progressively reduced in CCH mice. Additionally, expression of integrins αV and β5 in hippocampal neurons, microglia, and astrocytes decreased post-CCH. FAE effectively enhanced both peripheral and central irisin expression. Increased endogenous irisin levels inhibited CCH-induced hippocampal neuronal apoptosis and microglial activation, thereby promoting neuronal survival and partially ameliorating white matter injury. These changes led to improvements in memory, motor function, and anxiety- and depression-like behaviors. Mechanistically, the neuroprotective effects of irisin were mediated by enhanced hippocampal neuronal and microglial autophagy through increased AMPK phosphorylation and decreased mTOR phosphorylation-effects abolished by CT treatment.</p><p><strong>Conclusion: </strong>Our findings demonstrate that enhancing endogenous irisin via FAE mitigates CCH-induced neuronal apoptosis, microglial activation, cognitive impairment, and affective behavioral deficits by promoting autophagy through the integrin αVβ5/AMPK/mTOR signaling pathway.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"168"},"PeriodicalIF":9.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528361","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":"CXCR4 and CXCR6 dually limit T cell entry into the polyomavirus-infected brain.","authors":"Kalynn M Alexander, Elia Afanasiev, Arrienne B Butic, Ge Jin, Mofida Abdelmageed, Anirban Paul, Jo Anne Stratton, Aron E Lukacher, Samantha A Spencer","doi":"10.1186/s12974-025-03496-2","DOIUrl":"10.1186/s12974-025-03496-2","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"169"},"PeriodicalIF":9.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528429","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":"Genetically-engineered Salmonella typhimurium expressing FGF21 promotes neurological recovery in ischemic stroke via FGFR1/AMPK/mTOR pathway.","authors":"Dongchen Xu, Min Wen, Bingwa Lebohang Anesu, Xijun Chen, Yuhao Chen, Wenqi Qian, Chenguang Yang, Jin Hai Zheng, Yinan Zhou, Haoqi Ni, Kunlin Jin, Qichuan Zhuge, Su Yang","doi":"10.1186/s12974-025-03498-0","DOIUrl":"10.1186/s12974-025-03498-0","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke (IS) remains a leading cause of mortality and disability, with limited therapeutic options due to poor drug delivery to ischemic lesions. To address this challenge, an engineered Salmonella based therapeutic method for targeted drug delivery and long-term treatment is herein designed to mitigate ischemic damage.</p><p><strong>Methods: </strong>We engineered an attenuated luminescent Salmonella typhimurium (S.t -ΔpG) strain with an L-arabinose-inducible pBAD system to secrete bioactive FGF21. C57BL/6 mice were used to to measure neuron apoptosis and the activity of immune cells following IS induction plus S.t-ΔpG injection. Bioluminescence imaging was applied for bacterial colonization. ELISA and glucose uptake assays were performed to detect FGF21 secretion and the bioactivity. Neurological tests, TTC staining, and TUNEL labeling were used to assess the therapeutic effects of barterially secreted FGF21. Immunofluorescence assay of FGF21/FGFR1 dominant pathway was explored to investigate neuroprotective mechanism, while IBA-1 staining, CD3/CD68 immunostaining, cytokine profiling, and hepatorenal histopathology were detected to evaluate biosecurity.</p><p><strong>Results: </strong>S.t-ΔpG^FGF21 selectively colonized peri-infarct regions and secreted functional FGF21, reducing neurologic deficits (48%) and infarct volume (46%) versus controls (p < 0.01). Mechanistically, immunofluorescence demonstrated that bacterially secreted FGF21 activated neuronal FGFR1/AMPK/mTOR pathway to enhance autophagy, whereas autophagy inhibition abolished its neuroprotection. Further, bacterial exclusion from neuron was validated via MAP2/NeuN plus Salmonella co-staining in primary neuron cells and brain tissue. Critically, CD3/CD68 immunostaining, serum cytokine profiling, and hepatorenal histopathology confirmed the long-term biosafety of this approach.</p><p><strong>Conclusion: </strong>Our study presents a novel, Salmonella - based platform for targeted and sustained FGF21 delivery, offering a promising therapeutic strategy for ischemic stroke with robust efficacy and minimal systemic toxicity.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"170"},"PeriodicalIF":9.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528362","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}