Journal of Neuroinflammation最新文献

{"title":"A systematic review of the causes and consequences of spreading depolarization in neuroinflammation; implications for neurovascular disorders.","authors":"Faheem Anwar, Olivia Grech, Caroline W Mugo, James A Roberts, Jessica C Hubbard, Chloe N Thomas, Alexandra J Sinclair, Lisa J Hill","doi":"10.1186/s12974-025-03503-6","DOIUrl":"10.1186/s12974-025-03503-6","url":null,"abstract":"<p><strong>Background: </strong>Spreading depolarization (SD) is a wave of neuronal and glial depolarization observed in various neurological conditions, including stroke, traumatic brain injury, subarachnoid haemorrhage, and migraine aura. This depolarization disrupts ion homeostasis, creating high energy demand for recovery. While healthy tissue can compensate, pathological tissue may develop ischemia, worsening brain injury and outcomes. Identifying inflammatory mediators that exacerbate neuroinflammation after SD could guide targeted therapies. This review aimed to explore both the neuroinflammatory effects of SD and the impact of experimentally induced inflammatory states on SD characteristics.</p><p><strong>Methods: </strong>PubMed and Scopus were systematically searched for preclinical studies that examined the effects of SD on inflammation, and the effects of an inflammatory state on SD responses. Data extracted included authors, publication details, study type, animal characteristics, group sizes, exclusions, relevant findings, and limitations. Additional details were collected for studies on SD and neuroinflammation, including induction methods, inflammatory markers and SD characteristics in altered inflammatory states.</p><p><strong>Results: </strong>Several studies indicated that SD triggered a robust neuroinflammatory response, marked by upregulation of cytokines-interleukin-1β, tumour necrosis factor-α, and interleukin-6-alongside transcription factors such as nuclear factor kappa B, and activation of astrocytes and microglia. Key mediators including toll-like receptors, cyclooxygenase-2 and high mobility group box 1 were also implicated, with evidence of neurogenic involvement via the release of calcitonin gene-related peptide. Differences in inflammatory responses were identified between single and multiple SD induction. Studies measuring the effect of altered inflammatory states on SD propagation were limited. Models of peripheral inflammation and non-demyelinating autoimmune encephalomyelitis did not lead to significant alterations in SD characteristics. However, administration of tumour necrosis factor was able to reduce SD amplitude, suggesting a possible neuroprotective effect.</p><p><strong>Conclusion: </strong>This review suggests potential mechanisms underlying the role of SD in neurological disorders. While SD is associated with inflammatory markers, evidence for the impact of heightened inflammatory states on cortical susceptibility to SD remains limited. Significant methodological variability and inflammatory disease models underscores the need for standardization to validate these findings. Further research into these mechanisms could identify novel therapeutic targets to mitigate SD-related neuroinflammation in neurological disorders.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"178"},"PeriodicalIF":9.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600741","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":"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":"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":"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}

{"title":"B cells are not drivers of stromal cell activation during acute CNS infection.","authors":"Brendan T Boylan, Mihyun Hwang, Elyse Brozost, Hyunsuk Oh, Alexei V Tumanov, Antoine Louveau, Cornelia C Bergmann","doi":"10.1186/s12974-025-03491-7","DOIUrl":"10.1186/s12974-025-03491-7","url":null,"abstract":"<p><strong>Background: </strong>CNS stromal cells, especially fibroblasts and endothelial cells, support leukocyte accumulation through upregulation of adhesion molecules and lymphoid chemokines. While chronically activated fibroblast networks can drive pathogenic immune cell aggregates known as tertiary lymphoid structures (TLS), early stromal cell activation during CNS infection can support anti-viral T cells. However, the cell types and factors driving early stromal cell activation is poorly explored.</p><p><strong>Aims: </strong>A neurotropic murine coronavirus (mCoV) infection model was used to better characterize signals that promote fibroblast networks supporting accumulation of antiviral lymphocytes. Based on the early appearance of IgD⁺ B cells with unknown functions during several CNS infections, we probed their potential to activate stromal cells through lymphotoxin β (LTβ), a molecule critical in maintaining fibroblast-networks in lymphoid tissues as well as promoting TLS in autoimmunity and cancers.</p><p><strong>Results: </strong>Kinetic analysis of stromal cell activation in olfactory bulbs and brains revealed that upregulation of adhesion molecules and lymphoid chemokines Ccl19, Ccl21 and Cxcl13 closely tracked viral replication. Immunohistochemistry revealed that upregulation of the fibroblast marker podoplanin (PDPN) at meningeal and perivascular sites mirrored kinetics of RNA expression. Moreover, both B cells and T cells colocalized to areas of PDPN reactivity, supporting a potential role in regulating stromal cell activation. However, specific depletion of LTβ from B cells using Mb1-creERT2 x Ltβ^fl/fl mice had no effect on T or B cell recruitment or viral replication. B cell depletion by anti-CD20 antibody also had no adverse effects. Surprisingly, LTβR agonism reduced viral control and parenchymal T cell localization despite increasing stromal cell lymphoid chemokines and PDPN. Additional assessment of direct stromal cell activation by the viral RNA mimic poly I:C showed induction of Pdpn and Ccl19 preceding Ltb.</p><p><strong>Conclusions: </strong>Neither B cell-derived LTβ or B cells are primary drivers of stromal cell activation networks in the CNS following mCoV infection. Although supplementary agonist mediated LTβR engagement confirmed a role for LTβ in enhancing PDPN and lymphoid chemokine expression, it impeded T cell migration to the CNS parenchyma and viral control. Our data overall indicate that stromal cells can integrate LTβR signals to tune their activation, but that LTβ is not necessarily essential and can even dysregulate protective antiviral T cell functions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"165"},"PeriodicalIF":9.3,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512060","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}