Inflammation最新文献

{"title":"LncRNA SNHG7/miR-181b-5p/TLR4 Activates Inflammation And Promotes Pyroptosis Through NF-κB Signaling in Diabetic Nephropathy.","authors":"Min Zhang, Sheng-Jiang Xue, Feng Yang, Meng Xiao, Yong-Bo Tang, Ying Wu","doi":"10.1007/s10753-025-02295-4","DOIUrl":"https://doi.org/10.1007/s10753-025-02295-4","url":null,"abstract":"<p><p>MiR-181b-5p plays a critical role in the pyroptosis and injury of kidney tubular cells in diabetic kidney disease (DKD). The long noncoding RNA (lncRNA) small nucleolar RNA hostgene 7 (SNHG7) has been shown to bind to and inhibit the function of miR-181b-5p. However, the precise role of SNHG7 in DKD remains unclear. To address this, the current study measured the expression levels of SNHG7, miR-181b-5p, and Toll-like receptor 4 (TLR4) using RT-qPCR analysis of renal biopsies from both normal individuals and patients with DKD. An in vitro DKD model was subsequently established by exposing HK-2 cells to high glucose (HG). In both DKD tissues and HG-stimulated HK-2 cells, SNHG7 and TLR4 levels were significantly elevated, while miR-181b-5p levels were markedly reduced. Knockdown of SNHG7 resulted in multiple beneficial effects: it effectively attenuated high glucose-induced lactate dehydrogenase (LDH) leakage, restored cell viability, inhibited the production of inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 18 (IL-18), and interleukin 1β (IL-1β), and suppressed the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3)/acysteinyl aspartate-specific proteinase 1 (caspase-1)/gasdermin D (GSDMD) pathway. Mechanistically, SNHG7 functions as a molecular sponge for miR-181b-5p, while miR-181b-5p directly targets TLR4, collectively regulating nuclear factor-kappaB (NF-κB) pathway activation. Moreover, inhibition of miR-181b-5p or up-regulation of TLR4 reversed the protective effects of SNHG7 knockdown. Additionally, co-transfection of a TLR4 over-expression vector with a miR-181b-5p mimic counteracted the effects of miR-181b-5p overexpression on cell viability, LDH leakage, and the expression of inflammatory factors and pyroptosis-related molecules. In summary, SNHG7 acts as a molecular sponge for miR-181b-5p, promoting inflammation and pyroptosis in DKD, which in turn regulates TLR4 expression and the NF-κB signaling pathway.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Immunotherapy with Allergen-Loaded Extracellular Vesicles from Mast Cells Alleviates Allergic Asthma Inflammation in a Murine Model.","authors":"Liao Huanjin, Peng Xia, Yin Yue, Ge Yiqing, Li Yanning, Wang Juan, Li Jia, Lin Lihui, Li Li, Xie Guogang","doi":"10.1007/s10753-025-02307-3","DOIUrl":"https://doi.org/10.1007/s10753-025-02307-3","url":null,"abstract":"<p><p>Allergen immunotherapy (AIT) is the only treatment that can alter the course of allergic diseases by inducing immune tolerance through long-term, repeated low-dose allergen exposure. Nonetheless, AIT persistently faces challenges necessitating resolution, particularly in relation to treatment duration, the incidence of adverse reactions, and patient adherence. Extracellular vesicles (EVs) are promising drug delivery carriers for medications, vaccines, and targeted antibodies. Previously, we demonstrated that intravenous bone marrow-derived mast cell EVs (BMMC-EVs) can reduce allergic airway inflammation in asthmatic mice by interacting with free IgE. This study explores the potential of intranasally administered BMMC-EVs loaded with dermatophagoides farinae extracts to induce local immune tolerance and more effectively alleviate allergic asthma in mice. BMMC were co-cultured with the crude extract of dermatophagoides farina (DfE). BMMC-EVs-DfE were obtained and analyzed for the presence and concentration of DfE. The allergic asthma model was sensitized by intraperitoneal injection of DfE and Al(OH)₃ in BALB/c mice. Mice were immunized with PBS, BMMC-EVs-DfE, BMMC-EVs, and DfE intranasally. Then, mice were challenged with DfE after treatment. Effects of immunization were analyzed based on lung histology, bronchoalveolar lavage cell counts, lung cytokine levels, and plasma antibody levels. There were no deaths or signs of systemic toxicity noted in association with the BMMC-EVs-DfE, BMMC-EVs, and DfE immunized mice. BMMC-EVs-DfE immunization could decrease the total cells, macrophages and eosinophils number in bronchoalveolar lavage fluid (BALF), and attenuate goblet cell hyperplasia and MUC5AC expression in lung tissue. DfE specific IgE and IgG3 antibody, and histamine levels were significantly suppressed by BMMC-EVs-DfE immunization, while DfE specific IgG1 and IgG2a levels were increased. Moreover, BMMC-EVs-DfE can regulate the Th1/Th2 balance toward Th1 via increasing the IFN-γ and decreasing the IL-4 levels. We demonstrate here that BMMC-EVs-DfE could efficiently prevent allergic asthma inflammation, rebuild Th1/Th2 balance, reduce goblet hyperplasia and mucus production. BMMC-EVs-DfE as a platform for allergen delivery that effectively inhibits asthma airway inflammation.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcified Cartilage Zone Remodeling Induced by IL-1β Derived from Necrotic Subchondral Bone Initiates Cartilage Degeneration in Patients with Glucocorticoids-induced Osteonecrosis of the Femoral Head.","authors":"Pengbo Wang, Limei Shen, Ruitong Yang, Xu Wang, Xiangyu Wang, Yingkang Zhu, Ruiyu Liu","doi":"10.1007/s10753-025-02315-3","DOIUrl":"https://doi.org/10.1007/s10753-025-02315-3","url":null,"abstract":"<p><p>Glucocorticoids-induced osteonecrosis of the femoral head (GONFH) is characterized by progressive cartilage degeneration, yet the role of calcified cartilage zone (CCZ) remodeling in this process remains poorly understood. This study investigated how the inflammatory microenvironment within necrotic subchondral bone drove CCZ remodeling and subsequent cartilage degeneration. Using osteochondral tissues from GONFH patients and interleukin-1β (IL-1β)-treated hypertrophic chondrocytes induced by ATDC5 cells, we combined histology, immunohistochemistry, scanning electron microscopy, energy dispersive spectrometer, transmission electron microscopy, nanoindentation testing, enzyme linked immunosorbent assay and fluorescent tracking to evaluate morphological, biomechanical, and molecular changes. Our findings revealed that CCZ of GONFH exhibited significant thinning, matrix decomposition, demineralization, diminished mechanical strength, and increased porosity. Spatial analysis demonstrated a strong correlation between CCZ remodeling and site-specific cartilage degeneration. Notably, IL-1β was overexpressed in necrotic subchondral bone and the site deep zones of cartilage. It potently enhanced catabolic activity in hypertrophic chondrocytes, promoting matrix metalloproteinase expression while impairing mineralization capacity. This study uncovers a novel pathological cascade in GONFH: necrotic subchondral bone-derived IL-1β drives CCZ remodeling via biomechanical and biological pathways, leading to cartilage degeneration independent of femoral head collapse. Our findings highlight IL-1β as a critical therapeutic target, providing a rationale for subchondral bone-targeted anti-inflammatory strategies to mitigate GONFH progression.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nonstructural Protein 1 Mediates HMGB1 Release by Targeting Histone H1.0 After Respiratory Syncytial Virus Infection In Vivo and In Vitro.","authors":"Na Zhou, Siyi Che, Hui Zhai, Xiaohong Xie, Enmei Liu, Jun Xie","doi":"10.1007/s10753-025-02285-6","DOIUrl":"https://doi.org/10.1007/s10753-025-02285-6","url":null,"abstract":"<p><p>High mobility group box-1 (HMGB1) is implicated in airway inflammation during the late phase of respiratory syncytial virus (RSV) infection. Despite its recognized role, the specific mechanism underlying its release post-RSV infection remains ambiguous. The nonstructural protein 1 (NS1) has been associated with interactions with numerous host proteins, affecting diverse physiological processes, and it is speculated to be involved in the release of HMGB1. We utilized an in vivo model of RSV-infected mice and an in vitro model of RSV-infected A549 and 16HBE cells to investigate the role of NS1 in promoting HMGB1 release. Small interfering RNA was employed to deplete NS1, while lentiviral vectors were used for NS1 overexpression. The interaction between NS1 and H1.0 was confirmed by immunofluorescence analysis, immunoprecipitation, GST pull-down assays, surface plasmon resonance analysis and in silico study. Our study revealed that silencing the NS1 gene reduced the levels of HMGB1 protein and suppressed airway inflammation during the late stage of RSV infection. Depletion of NS1 led to decreased levels of intracellular and extracellular HMGB1 in A549 and 16HBE cells, while over-expression of NS1 increased HMGB1 expression. Furthermore, NS1 and HMGB1 directly interacted with histone H1.0, as confirmed by GST pull-down, surface plasmon resonance and in silico analyses. Overexpression of NS1 disrupted the binding of HMGB1 to H1.0, while silencing of NS1 enhanced their interaction. The research findings indicate that NS1 interacts with H1.0, thereby inhibiting the binding of HMGB1 to H1.0. Consequently, this interaction results in the release of HMGB1 into both the cytoplasm and the extracellular space.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium-Glucose Cotransporter 2 Inhibitor Ameliorate Angiotensin II-Induced Hypertension and Vascular Injury by Upregulating FGF21.","authors":"Manyu Dai, Zhuoran Jia, Huimin Wang, Peiyang Zheng, Yangcheng Xue, Ke Gong, Ren Zhao","doi":"10.1007/s10753-025-02309-1","DOIUrl":"https://doi.org/10.1007/s10753-025-02309-1","url":null,"abstract":"<p><p>Clinical trials have demonstrated Sodium-glucose cotransporter 2 inhibitors (SGLT2i) antihypertensive effects, yet their underlying mechanisms remain to be fully elucidated. Fibroblast growth factor 21 (FGF21) circulating levels are associated with hypertension in humans. This study aims to investigate the roles of SGLT2i and FGF21 in improving hypertension and their potential mechanisms. A mouse model of Ang II-induced hypertension was established. Wild-type (WT) C57BL/6 mice and FGF21 knockout (FGF21^-/-) mice were sequentially treated with Angiotensin II (Ang II) and dapagliflozin. Blood pressure was monitored. Cardiac structure was assessed using echocardiography. Serum FGF21 levels were measured, and the expression of fibroblast growth factor receptor 1 (FGFR1) in the thoracic aorta was quantified. Vascular pathology and oxidative stress responses were evaluated. Human aortic smooth muscle cells (HASMCs) were treated with Ang II or SGLT2i, and FGF21 was knocked down in HASMCs to explore its mechanism of action. SGLT2i increased the expression of FGF21 and FGFR. SGLT2i improved Ang II-induced systolic blood pressure elevation, myocardial hypertrophy, vascular wall thickening, fibrosis, and oxidative stress in WT mice. These protective effects were reduced in FGF21^-/- mice. Knockdown of FGF21 in HASMCs abolished the SGLT2i-induced upregulation of antioxidant markers and the downregulation of TGF-β and fibrosis-related proteins. SGLT2i-mediated blood pressure-lowering and vascular protective effects are primarily achieved through the activation of the FGF21/FGFR1.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics Analysis Reveals the Propagation Mechanism of Ferroptosis in Acute Kidney Injury.","authors":"Yu Hong, Qi An, Zheng Wang, Bin Hu, Yi Yang, Rui Zeng, Ying Yao","doi":"10.1007/s10753-025-02311-7","DOIUrl":"https://doi.org/10.1007/s10753-025-02311-7","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a prevalent and critical clinical condition characterized by high morbidity and mortality. Recently, numerous studies have implicated ferroptosis, an iron-dependent programmed cell death process, in the pathophysiology of AKI. Despite this, the mechanism underlying the widespread occurrence of ferroptosis in AKI remains elusive. To address this, our study analyzed snRNA-seq data from AKI and healthy renal tissues. The analysis revealed notable differences in ferroptosis activity within proximal tubule (PT) cells of AKI patients, specifically highlighting a strong correlation between ferroptosis and the expression of genes GPX4, FTH1, and FTL. Spatial transcriptomics confirmed that the genes GPX4, FTH1, and FTL play a crucial role in driving ferroptosis propagation in AKI. Furthermore, utilizing a mouse model of bilateral renal ischemia-reperfusion injury, we validated the emergence of ferroptosis mediated by these key genes following AKI. The findings from our in vivo experiments were consistent with the spatial transcriptomics data. Chromatin accessibility and transcription factor analysis identified KLF6 as a repressor of ferroptosis-related genes. An in-depth analysis of PT revealed a subpopulation closely associated with ferroptosis. The cellular microenvironment within this subpopulation may regulate ferroptosis through the SPP1 signaling pathway, ultimately influencing the outcome of PT following AKI. In conclusion, this study elucidates the crucial role of GPX4, FTH1, and FTL in ferroptosis propagation during AKI and underscores the potential therapeutic benefits of targeting ferroptosis in the management of AKI.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting SLC7 A11 Ameliorates Ulcerative Colitis by Promoting Efferocytosis Through the ERK1/2 Pathway.","authors":"Meiyi You, Jichang Li, Xin Wang, Yucun Liu, Shanwen Chen, Pengyuan Wang","doi":"10.1007/s10753-025-02312-6","DOIUrl":"https://doi.org/10.1007/s10753-025-02312-6","url":null,"abstract":"<p><strong>Objective and design: </strong>This study investigates the effect and underlying mechanism of targeting SLC7A11 in mitigating dextran sulfate sodium (DSS)-induced intestinal inflammation and injury in colitis.</p><p><strong>Methods: </strong>We utilized wild-type and SLC7A11^-/+ mice to assess the inflammatory damage in DSS-induced colitis in vivo. In vitro, colon tissues from patients with ulcerative colitis were analyzed to compare SLC7A11 expression between inflamed and non-inflamed regions. Further mechanistic insights were obtained using Caco-2 cells and bone marrow-derived dendritic cells (BMDCs).</p><p><strong>Results: </strong>In human colon tissues, SLC7A11 expression was significantly elevated in inflamed regions compared to non-inflamed areas, particularly in dendritic cells. In vivo inhibition of SLC7A11 markedly alleviated DSS-induced colitis symptoms. In vitro, suppressing SLC7A11 restored the integrity of the Caco-2 monolayer intestinal epithelial model. Both knockout and inhibition of SLC7A11 enhanced ERK1/2 phosphorylation and increased efferocytosis in BMDCs.</p><p><strong>Conclusions: </strong>Targeting SLC7A11 augments dendritic cell efferocytosis and preserves intestinal epithelial barrier function, potentially offering a therapeutic avenue for alleviating ulcerative colitis.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell RNA Sequencing Reveals the Immune Landscape of Granulomatous Mastitis.","authors":"Yao Zhou, Xianguang Deng, Hui Ruan, Xing Xue, Zixuan Hu, Jie Gong, Shiting Wu, Lifang Liu","doi":"10.1007/s10753-025-02310-8","DOIUrl":"https://doi.org/10.1007/s10753-025-02310-8","url":null,"abstract":"<p><p>Granulomatous mastitis (GM) is a form of non-lactational breast inflammation that is closely associated with autoimmune processes, however its underlying pathogenesis remains elusive. In this study, we employed single-cell RNA sequencing (scRNA-seq) to conduct a comparative analysis of GM lesion tissues versus normal breast tissues, thereby unveiling the immune profile of GM tissues. Our investigation centered on T and NK cells, macrophages, epithelial cells, and endothelial cells. Notably, we observed a substantial infiltration of immune cells in GM tissues, accompanied by immune disorders, an elevation in Th1 cell counts, enrichment of the toll-like receptor (TLR) pathway, and upregulation of various factors including interferon-γ (IFN-γ), C-C motif chemokine ligand 3 (CCL3), CCL4, chemokine (C-X-C motif) ligand (CXCL) 13, CD69, signal transducer and activator of transcription 1 (STAT1), and heat shock protein family A member 1A (HSPA1A). Furthermore, the macrophage subpopulations in GM tissues exhibited a transition to a pro-inflammatory phenotype, enriched for pathways such as interferon-γ (IFN-γ), IFN-α, interleukin-6/janus kinase/signal transducer and activator of transcription 3 (IL-6/JAK/STAT3), and tumor necrosis factor-α/nuclear factor-κB (TNF-α/NF-κB). Mammary luminal cells demonstrated an impaired estrogenic profile yet displayed upregulation of prolactin downstream signaling pathways, namely the JAK/STAT and mitogen-activated protein kinase (MAPK) pathways. Additionally, vascular endothelial cells were found to recruit immune cells and exhibited a prominent angiogenic profile in GM tissues. Cellular interaction analysis unveiled an intricate network of interactions between mesenchymal and immune cells. This study provides a comprehensive immune landscape of granulomatous mastitis and offers some potential therapeutic targets for the disease.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIPE2 Alleviates Sepsis-induced Lung Injury By Inhibiting PANoptosis in Murine Alveolar Macrophages.","authors":"Yuxuan Wang, Min Yuan, Jingxue Qin, Xue Chen, Zihan Lei, Qian Kong, Qian Wang, Xuemin Song, Xiaojing Wu","doi":"10.1007/s10753-025-02288-3","DOIUrl":"https://doi.org/10.1007/s10753-025-02288-3","url":null,"abstract":"<p><p>Sepsis-induced acute lung injury (ALI) is a life-threatening condition with high mortality rates, and its underlying mechanisms remain poorly understood. This study investigates the role of TNF-α-induced protein 8-like 2 (TIPE2) in modulating PANoptosis, an integrated form of programmed cell death that includes apoptosis, necroptosis, and pyroptosis, in the context of sepsis-induced lung injury. We utilized a cecal ligation and puncture (CLP) mouse model to examine the effects of TIPE2 knockout and overexpression on lung injury, inflammation, and cell death pathways. Our findings demonstrate that TIPE2 knockout exacerbates lung injury by promoting the abnormal activation of PANoptosis-related proteins, leading to increased inflammation and tissue damage. In contrast, overexpression of TIPE2 in macrophages significantly reduces these effects by inhibiting the ZBP1-dependent PANoptosis pathway via TRIF signaling. These results highlight the crucial role of TIPE2 in maintaining the balance between cell survival and death during sepsis and suggest that targeting TIPE2 could be a novel therapeutic strategy for treating sepsis-related lung injury.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute and Long-Term Consequences of Neonatal NMDA Blockade in the Cx3cr1 Knock-Out Mouse.","authors":"Felipe A Méndez, Mayra Itzel Torres-Flores, Benito Ordaz, Fernando Peña-Ortega","doi":"10.1007/s10753-025-02272-x","DOIUrl":"https://doi.org/10.1007/s10753-025-02272-x","url":null,"abstract":"<p><p>Neuron-microglia communication through the fractalkine pathway is a critical factor mediating microglial proliferation, migration, release of mediators, and clearance of cellular debris, as well as the function of neuronal NMDA receptors. Disruption of the fractalkine-mediated microglia-neuron communication is associated with divergent outcomes, from damaging to protective, in different neurological conditions (including schizophrenia and epilepsy). In the present work we explore the impact of the absence of the fractalkine receptor (CX3CR1) after neonatal blockade of NMDA receptors, which induces acute and long-term alterations in behavior, neuronal integrity and excitability. Wild-type (WT) and Cx3cr1^-/- (KO) mice of both sexes randomly received either a low (0.5 mg/kg) or high dose (1 mg/kg) of MK-801 (NMDA receptor antagonist) or saline, for five consecutive days, during early postnatal development. Neuronal apoptosis was assessed at a midpoint of the pharmacological protocol. Survival and growth rates were determined up to adulthood when innate behaviors, unconditioned anxiety, contextual memory and seizure susceptibility were evaluated, as well as hippocampal local field potential and sensory gating. CX3CR1 depletion and neonatal MK-801 treatment had a synergistic acute effect, increasing neuronal apoptosis and overall mortality. Both factors independently induced long-lasting impairments in the wide array of behavioral tasks assessed during adulthood. However, low MK-801 dose treatment greatly augmented the mortality of pentylenetetrazol-induced seizures in WT mice, an effect prevented by CX3CR1 depletion. MK-801 treatment induced a shift in the power spectrum of the hippocampal local field potential towards higher frequencies that was averted in Cx3cr1^-/- mice by an opposite shift. Our results reveal that CX3CR1 depletion severely increases the vulnerability to neonatal NMDA antagonism with additional complex interactions regarding cognitive and neurophysiological effects, which should be considered in the context of neuron-microglia miscommunication in many neurological disorders including schizophrenia and epilepsy.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}