Inflammation最新文献_第6页

USP43 Inhibits Intestinal Inflammation via TRAF4-mediated NF-κB Signaling. USP43通过traf4介导的NF-κB信号抑制肠道炎症。

IF 5.4 2区医学

Inflammation Pub Date : 2026-05-16 DOI: 10.1007/s10753-026-02509-3

Li Zhou, Dongliang Li, Yan Lv, Jian Fang, Yue Liu, Zhencheng Zhu, Xin Tang, Bo Zhang, Chenjiang Qu, Qiuhua Liu

{"title":"USP43 Inhibits Intestinal Inflammation via TRAF4-mediated NF-κB Signaling.","authors":"Li Zhou, Dongliang Li, Yan Lv, Jian Fang, Yue Liu, Zhencheng Zhu, Xin Tang, Bo Zhang, Chenjiang Qu, Qiuhua Liu","doi":"10.1007/s10753-026-02509-3","DOIUrl":"10.1007/s10753-026-02509-3","url":null,"abstract":"Ulcerative colitis (UC) is a chronic inflammatory intestinal disorder; however, its exact pathophysiological mechanisms remain elusive. Through integrated RNA-seq and proteome analyses, we revealed that ubiquitin-specific protease 43 (USP43) expression is significantly decreased in dextran sulfate sodium (DSS)-induced colitis. USP43 expression was also lower in UC patients than that in healthy controls. Furthermore, USP43 deficiency in mice exacerbated DSS-induced colitis. In lipopolysaccharide (LPS)-treated RAW264.7 cells, USP43 overexpression inhibited, whereas USP43 knockdown promoted the phosphorylation of p65 and the production of proinflammatory cytokines; NF-κB-specific inhibitor JSH-23 reversed the facilitatory effect of USP43 knockdown on inflammatory cytokines. Mechanistically, USP43 interacts with and deubiquitinates TRAF4, thereby inhibiting NF-κB signaling and reducing proinflammatory cytokine levels. Importantly, TRAF4 overexpression partially reversed the increase in LPS-mediated NF-κB activation caused by USP43 knockdown. Collectively, our findings highlight a novel role for USP43 in suppressing intestinal inflammation through the inhibition of TRAF4-mediated NF-κB activation. These results reveal a new mechanism involving the USP43/TRAF4 axis in the regulation of intestinal inflammation.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147948341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacological Characterization of GLPG3667, a Tyrosine Kinase 2-Selective Inhibitor, for the Treatment of Inflammatory and Autoimmune Diseases. 酪氨酸激酶2选择性抑制剂GLPG3667治疗炎症和自身免疫性疾病的药理特性

IF 5.4 2区医学

Inflammation Pub Date : 2026-05-16 DOI: 10.1007/s10753-026-02519-1

Céline Cottereaux, May-Linda Lepage, Isabelle Parent, Maikel Colli, An Van de Water, Emilie Lagoutte, Christelle David, Maarten Van Balen, Adrien Cosson, Roland Blanque, Kenji Shoji, Mia Jans, Laetitia Furio, Steven Van der Plas, Reginald Brys, David Amantini, René Galien

{"title":"Pharmacological Characterization of GLPG3667, a Tyrosine Kinase 2-Selective Inhibitor, for the Treatment of Inflammatory and Autoimmune Diseases.","authors":"Céline Cottereaux, May-Linda Lepage, Isabelle Parent, Maikel Colli, An Van de Water, Emilie Lagoutte, Christelle David, Maarten Van Balen, Adrien Cosson, Roland Blanque, Kenji Shoji, Mia Jans, Laetitia Furio, Steven Van der Plas, Reginald Brys, David Amantini, René Galien","doi":"10.1007/s10753-026-02519-1","DOIUrl":"10.1007/s10753-026-02519-1","url":null,"abstract":"Janus kinase inhibitors have demonstrated efficacy in treating inflammatory and autoimmune diseases; however, several concerns restrict their use in medical practice. One member of this kinase family, tyrosine kinase 2 (TYK2), recently attracted attention owing to the limited number of key inflammatory cytokine pathways it mediates (type I interferon, interleukin [IL]-12/IL-23, and IL-10 family pathways) and the numerous genetic studies associating polymorphisms of the TYK2 gene with protection against several inflammatory and autoimmune diseases. In that regard, we discovered a selective, reversible, ATP-competitive inhibitor of TYK2, GLPG3667. We present the selectivity of GLPG3667 in biochemical, cellular, and human whole blood assays. In vitro, GLPG3667 inhibited the IL-12- and IL-23-induced polarization of T helper (TH)1 and TH17, respectively, but was shown to have a more limited impact on the IL-10 pathway and the anti-inflammatory effects of IL-10 in vitro. Pharmacodynamic analyses performed during phase 1 trials, in which healthy volunteers received GLPG3667 orally, confirmed the selectivity of the compound for TYK2-dependent pathways. In addition, following an in vivo challenge in these healthy volunteers, GLPG3667 inhibited the biological effects of interferon-α, supporting its potential use in treating several inflammatory and autoimmune diseases.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Erosion or Explosion: Integrated Single-Cell Transcriptomics Reveals Cellular Heterogeneity in Aortic Aneurysm and Dissection. 侵蚀或爆炸：综合单细胞转录组学揭示了主动脉瘤和夹层的细胞异质性。

IF 5.4 2区医学

Inflammation Pub Date : 2026-05-12 DOI: 10.1007/s10753-026-02523-5

Heng Wang, Keyi Fan, Yaling Li, Ziyan Wang, Keyang Xu, Maolin Qiao, Taoran Zhao, Chaonan Fan, Guoping Zheng

{"title":"Erosion or Explosion: Integrated Single-Cell Transcriptomics Reveals Cellular Heterogeneity in Aortic Aneurysm and Dissection.","authors":"Heng Wang, Keyi Fan, Yaling Li, Ziyan Wang, Keyang Xu, Maolin Qiao, Taoran Zhao, Chaonan Fan, Guoping Zheng","doi":"10.1007/s10753-026-02523-5","DOIUrl":"10.1007/s10753-026-02523-5","url":null,"abstract":"Aortic aneurysm (AA) and aortic dissection (AD) are life-threatening vascular diseases characterized by progressive wall degeneration and structural failure. However, the cellular mechanisms underlying their progression and rupture remain poorly understood. We performed integrative single-cell RNA sequencing analysis on four human aortic datasets, including thoracic aortic dissection (TAD), thoracic aortic aneurysm (TAA), abdominal aortic aneurysm (AAA), and ruptured AAA. We identified disease-specific patterns of immune infiltration and vascular structural cell loss. Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) were reduced in AA but increased in AD. In ruptured AAA, structural cells were nearly absent, with immune cells predominating. In TAD, VSMCs and ECs exhibited marked phenotypic plasticity, transdifferentiating into multiple cell subtypes. Notably, we identified macrophage-like VSMCs and ECs in AD mouse models. Cell-cell communication analysis revealed that macrophages communicated with VSMCs and ECs via the CXCL, IL1B, and SPP1 signaling axes. Importantly, REL, a member of the NF-κB transcription factor family, was identified as a convergent node integrating these inflammatory signals. This study delineates disease-specific transdifferentiation trajectories of ECs and VSMCs during AA and AD progression. Inflammatory macrophages regulate this phenotypic switching via CXCL, IL1B, and SPP1 signaling, activating REL-driven transcriptional programs that compromise vascular integrity. These findings uncover fundamental differences in cellular heterogeneity and injury mechanisms between AA and AD, offering potential therapeutic targets for preventing disease progression and rupture.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13337744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147928936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of ATF3 as a Potential Key Biomarker for Hypertensive Nephropathy via Single-Cell Transcriptome Sequencing. 通过单细胞转录组测序鉴定ATF3作为高血压肾病的潜在关键生物标志物。

IF 5.4 2区医学

Inflammation Pub Date : 2026-05-11 DOI: 10.1007/s10753-026-02515-5

Fangyan Tan, Rong Hu, Jianlin Du, Ya Song

{"title":"Identification of ATF3 as a Potential Key Biomarker for Hypertensive Nephropathy via Single-Cell Transcriptome Sequencing.","authors":"Fangyan Tan, Rong Hu, Jianlin Du, Ya Song","doi":"10.1007/s10753-026-02515-5","DOIUrl":"10.1007/s10753-026-02515-5","url":null,"abstract":"Hypertensive Nephropathy (HTN) is a leading cause of end-stage renal disease (ESRD). Its pathogenesis is complex, involving heterogeneous alterations across multiple cell types. Currently, there is a lack of specific biomarkers capable of early detection of renal injury and reflecting molecular pathological characteristics. We performed an integrated analysis of single-cell RNA sequencing (scRNA-seq) data derived from renal tissue samples of HTN patients and healthy controls. Cell subpopulations were identified via dimensionality reduction and clustering, and key genes were screened using differential expression analysis. Furthermore, we employed functional enrichment analysis, non-negative matrix factorization (NMF), pseudotime trajectory analysis, and transcription factor regulatory network analysis to investigate biological functions and cell-type-specific expression patterns. Validation was conducted using both in vivo and in vitro models. We identified a regulatory network centered on activating transcription factor 3 (ATF3) within renal tubular epithelial cells of HTN tissues. Subsequent validation demonstrated that ATF3 is significantly upregulated in HTN, suggesting it serves as a critical stress response factor mediating renal tissue injury. Mechanistically, our data suggests that ATF3 may participate in the pathological progression of HTN by regulating oxidative stress signaling pathways via FOSB. Based on single-cell sequencing and experimental validation, this study identifies ATF3 as a promising key biomarker for HTN and provides a novel molecular target for its diagnosis and targeted therapy.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13333566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147868060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nrf2 Protects Against Lipoteichoic Acid-Induced Acute Lung Injury By Suppressing SLC24A2-Mediated Ferroptosis. Nrf2通过抑制slc24a2介导的铁凋亡来保护脂质胆酸诱导的急性肺损伤。

IF 5.4 2区医学

Inflammation Pub Date : 2026-05-09 DOI: 10.1007/s10753-026-02499-2

Ri-Xiang Huang, Tao Lu, Nan-Nan Liu, Jiao-Jiao Sun, Jun Zhu, Min Chen, Dan Chen, Ya-Xian Wu, Yuan Weng, Zhi-Qiang Wang

{"title":"Nrf2 Protects Against Lipoteichoic Acid-Induced Acute Lung Injury By Suppressing SLC24A2-Mediated Ferroptosis.","authors":"Ri-Xiang Huang, Tao Lu, Nan-Nan Liu, Jiao-Jiao Sun, Jun Zhu, Min Chen, Dan Chen, Ya-Xian Wu, Yuan Weng, Zhi-Qiang Wang","doi":"10.1007/s10753-026-02499-2","DOIUrl":"10.1007/s10753-026-02499-2","url":null,"abstract":"Acute lung injury (ALI) is a severe inflammatory syndrome characterized by epithelial and endothelial injury, increased pulmonary vascular permeability, and impaired gas exchange. ALI often involves ferroptosis, an iron-dependent form of oxidative cell death. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of antioxidant defenses, but its role in ALI-related ferroptosis is not well understood. In this study, NRF2 knockout (KO) mice were utilized for transcriptomic analysis to investigate the role of NRF2 in ALI. NRF2 deficiency significantly exacerbated lung injury and ferroptosis, and upregulated the expression of the calcium transporter gene solute carrier family 24 member 2 (SLC24A2). Calcium overload was closely associated with increased SLC24A2 expression and contributed to the development of ferroptosis. These findings were validated in vitro: knockdown of NRF2 in lung epithelial cells enhanced susceptibility to ferroptosis, whereas overexpression of NRF2 attenuated ferroptotic cell death. Conversely, silencing SLC24A2 reduced intracellular calcium overload and suppressed ferroptosis. These results suggest that there may be a regulatory axis between NRF2 and SLC24A2, which has a potential association with inflammation and ferroptosis signals related to acute lung injury (ALI). However, further studies are required to clarify the causal relationship and its consistency across different models, thereby evaluating the feasibility of this axis as a potential therapeutic target.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13328348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: miR-221 Exerts Antiviral and Anti-Inflammatory Effects against HSV-1 Through Direct Repression of CAMK2A and Immune Pathway Activation. 更正：miR-221通过直接抑制CAMK2A和免疫通路激活对HSV-1发挥抗病毒和抗炎作用。

IF 5 2区医学

Inflammation Pub Date : 2026-05-08 DOI: 10.1007/s10753-026-02517-3

Jiahao Xu, Lianhong Xu, Die Hu, Ying Zhang, Yongfang Wang, Zhihua Yun

引用次数: 0

Peripheral Circulating Exosomes Induce Sepsis-associated Liver Injury by Up-regulating STAT1 to Promote Autophagy and Regulating the SLC7A11-GSH-GPX4 Axis to Promote Ferroptosis. 外周循环外泌体通过上调STAT1促进自噬和调节SLC7A11-GSH-GPX4轴促进铁凋亡诱导脓毒症相关肝损伤

IF 5.4 2区医学

Inflammation Pub Date : 2026-05-02 DOI: 10.1007/s10753-026-02495-6

Yu-Jia Tang, Xue Du, Bing Yin, Hui-Ying Liu, Yi-Jin Tang, Zi-Yue Zhang, Qing-Min Meng, Yan Zhang, Jia-Le Deng, Yao Li, Pei-Lin Yang, Kai Kang, Ming-Yan Zhao, Yang Gao

{"title":"Peripheral Circulating Exosomes Induce Sepsis-associated Liver Injury by Up-regulating STAT1 to Promote Autophagy and Regulating the SLC7A11-GSH-GPX4 Axis to Promote Ferroptosis.","authors":"Yu-Jia Tang, Xue Du, Bing Yin, Hui-Ying Liu, Yi-Jin Tang, Zi-Yue Zhang, Qing-Min Meng, Yan Zhang, Jia-Le Deng, Yao Li, Pei-Lin Yang, Kai Kang, Ming-Yan Zhao, Yang Gao","doi":"10.1007/s10753-026-02495-6","DOIUrl":"10.1007/s10753-026-02495-6","url":null,"abstract":"Peripheral exosomes have been implicated in the pathogenesis of multiple organ dysfunction during sepsis. However, their role in sepsis-associated liver injury (SALI) remains unclear. This study aimed to investigate the effects of circulating exosomes on hepatic injury and to elucidate the underlying molecular mechanisms of SALI. A murine sepsis model was established via intraperitoneal injection of lipopolysaccharide (LPS). Peripheral exosomes were isolated and co-cultured with murine hepatocytes (AML12 cells). RNA sequencing identified Signal transducer and activator of transcription 1 (STAT1) as a key regulator in exosome-induced liver injury. Since STAT1 functions upstream of the ferroptosis-related solute carrier family 7 member 11 (SLC7A11)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, further in vivo and in vitro experiments were conducted to clarify its mechanistic role. In vitro, exosomes derived from septic mice enhanced inflammatory responses in AML12 cells via STAT1-mediated autophagy and modulation of the SLC7A11-GSH-GPX4 axis, leading to ferroptosis. Inhibition of STAT1 abrogated these effects, whereas STAT1 overexpression potentiated them. In vivo, septic exosomes (sep-Exo) induced liver injury in mice, while suppression of STAT1 abolished the regulatory effects of sep-Exo on ferroptosis, autophagy, and hepatic inflammation. Our findings reveal a novel mechanism underlying SALI, whereby peripheral exosomes upregulate STAT1 to induce autophagy and modulate the SLC7A11-GSH-GPX4 axis, thereby promoting ferroptosis and hepatic inflammation during sepsis.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13279614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The miR-155-5p/SOCS1/NF-κB Axis Regulates Airway Smooth Muscle Dysfunction and is a Potential Therapeutic Candidate of Chronic Obstructive Pulmonary Disease. miR-155-5p/SOCS1/NF-κB轴调节气道平滑肌功能障碍，是慢性阻塞性肺疾病的潜在治疗候选者。

IF 5.4 2区医学

Inflammation Pub Date : 2026-04-27 DOI: 10.1007/s10753-026-02516-4

Kaijun Zhang, Xin Zou, Zhiyi Ma, Weihong Wang, Yongming Wu, Zhaosheng Lin, Machang Luo, Rongzhang Liang, Xiaoming Wu

{"title":"The miR-155-5p/SOCS1/NF-κB Axis Regulates Airway Smooth Muscle Dysfunction and is a Potential Therapeutic Candidate of Chronic Obstructive Pulmonary Disease.","authors":"Kaijun Zhang, Xin Zou, Zhiyi Ma, Weihong Wang, Yongming Wu, Zhaosheng Lin, Machang Luo, Rongzhang Liang, Xiaoming Wu","doi":"10.1007/s10753-026-02516-4","DOIUrl":"10.1007/s10753-026-02516-4","url":null,"abstract":"Airway smooth muscle cell (ASMC) dysfunction, including altered cell viability, proliferation-apoptosis imbalance, and proinflammatory activation, contributes to the pathogenesis of chronic obstructive pulmonary disease (COPD) associated inflammatory processes. We investigated the role of the miR-155-5p/SOCS1/NF-κB axis in these processes. We performed integrative analyses of GEO dataset mining (GSE5058), clinical samples from COPD patients, a mouse model of LPS/cigarette smoke–induced pulmonary inflammation, and mechanistic in vitro studies in ASMCs. The expression levels of miR-155-5p and SOCS1 were assessed by RT-qPCR and Western blotting. ASMC viability, apoptosis, invasion, cell cycling, and cytokine production were tested. Target interaction was validated by dual-luciferase reporter assay, and pathway involvement was assessed by analysis of the NF-κB signaling. miR-155-5p expression increased, and SOCS1 decreased in COPD lung tissues and serum (both p < 0.001), with an inverse correlation (r = − 0.48, p < 0.005). In mice, elevated miR-155-5p was associated with greater lung injury, higher TNF-α/IL-6 production, increased Cyclin D1 and phosphorylated NF-κB p65, and reduced p21, SOCS1, and cleaved caspase-3 (all p < 0.05). In ASMCs, miR-155-5p promoted cell viability, invasion, S-phase entry, apoptosis resistance, and cytokine production (all p < 0.05). miR-155-5p directly bound the SOCS1 3′UTR. miR-155-5p inhibition or SOCS1 overexpression attenuated NF-κB activation and rescued these phenotypes; SOCS1 overexpression reduced ~ 70% of miR-155-5p mimic–induced changes. The miR-155-5p/SOCS1/NF-κB axis contributes to ASMC dysfunction in COPD, supporting miR-155-5p as a potential therapeutic candidate.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13253646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Histamine Four Receptor Regulates LFA-1 But Not Mac-1 -Dependent Neutrophil Adhesion and Inflammatory Functions. 组胺4受体调节LFA-1但不调节Mac-1依赖性中性粒细胞粘附和炎症功能。

IF 5.4 2区医学

Inflammation Pub Date : 2026-04-27 DOI: 10.1007/s10753-026-02508-4

Karim Dib

{"title":"The Histamine Four Receptor Regulates LFA-1 But Not Mac-1 -Dependent Neutrophil Adhesion and Inflammatory Functions.","authors":"Karim Dib","doi":"10.1007/s10753-026-02508-4","DOIUrl":"10.1007/s10753-026-02508-4","url":null,"abstract":"Neutrophils incubated on ICAM-1- or fibrinogen- coated plates produced histamine in response to fMLP indicating that histamine may be an intermediary chemoattractant promoting β2 integrin-dependent adhesion. fMLP, but not histamine or the histamine four receptor (H4R) agonist VUF 8430, augmented adhesion of neutrophils, or neutrophil-like PLB-985 cells, to fibrinogen, a Mac-1 ligand. This result may be explained by the fact that fMLP, but not histamine, augmented intracellular calcium, a pre-requisite for Mac-1 expression on the cell surface. fMLP- induced Mac-1- dependent adhesion was not affected by histamine or VUF 8430. fMLP induces conformational activation of LFA-1, but neutrophil adhesion to ICAM-1 was not augmented by fMLP. Histamine did not augment neutrophil adhesion to ICAM-1, as histamine does not induce conformational activation of LFA-1. Importantly, fMLP augmented neutrophil adhesion to ICAM-1 when combined with histamine or VUF 8430. Thus, activation of the H4R and the formyl peptide receptor 1 may be required to augment LFA-1 avidity. Histamine activated Rap1, Rac1/2 and Cdc42 in neutrophil-like PLB-985 cells. These effects were blocked by Src tyrosine kinase inhibitors (for Rap1 and Rac1/2 but not Cdc42). VUF 8430 activated these GTPases in PLB-985 cells and neutrophils indicating that the H4R controls neutrophil functions. Intriguingly, histamine inhibited fMLP-induced specific granule but not azurophil granule exocytosis by adherent neutrophils. Histaminase is present in specific granules. Therefore, inhibition of specific granule exocytosis may be a mechanism to limit the catabolism of histamine produced by adherent neutrophils to allow H4R-mediated inflammation through activation of monomeric GTPases and LFA-1.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13253667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of New P2X7R Antagonists on Retinal Inflammatory Degenerative Conditions. 新型P2X7R拮抗剂对视网膜炎性退行性疾病的影响。

IF 5.4 2区医学

Inflammation Pub Date : 2026-04-25 DOI: 10.1007/s10753-026-02513-7

Chiara Bianca Maria Platania, Federica Conti, Maria Consiglia Trotta, Nicoletta Marchesi, Sonia Panico, Francesca Lazzara, Caterina Claudia Lepre, Marina Russo, Carlo Gesualdo, Francesca Simonelli, Michele D'Amico, Filippo Drago, Alessia Pascale, Settimio Rossi, Valeria Tarallo, Claudio Bucolo

{"title":"Effects of New P2X7R Antagonists on Retinal Inflammatory Degenerative Conditions.","authors":"Chiara Bianca Maria Platania, Federica Conti, Maria Consiglia Trotta, Nicoletta Marchesi, Sonia Panico, Francesca Lazzara, Caterina Claudia Lepre, Marina Russo, Carlo Gesualdo, Francesca Simonelli, Michele D'Amico, Filippo Drago, Alessia Pascale, Settimio Rossi, Valeria Tarallo, Claudio Bucolo","doi":"10.1007/s10753-026-02513-7","DOIUrl":"10.1007/s10753-026-02513-7","url":null,"abstract":"Purinergic receptor (P2X7R), an adenosine triphosphate (ATP) gated nonselective cation channel, is an emerging target for several neurodegenerative conditions, including retinal degeneration. In particular, P2X7R has an established role in multiple inflammatory and immune responses, being implicated in the formation and activation of NLRP3 inflammasome leading to inflammatory priming and release of immune cytokines. Despite several efforts in P2X7R antagonist design, no drugs have reached the market yet. In this perspective, through an integrated in silico and in vitro approach, we aimed to repurpose FDA approved drugs in search of novel safe treatments for retinal degenerative diseases, where P2X7R has been found to play a detrimental role. Virtual screening of about 10,000 FDA approved drugs identified 6 putative P2X7 antagonists. Three out of these six compounds inhibited hP2X7, but not rat receptors, while only one compound, tipranavir, inhibited also mouse P2X7R. Then, for these three P2X7R antagonists, namely bazedoxifene, teniposide and tipranavir, we have evaluated the in vitro tolerability by treating immortalized human Müller cells (MIO-M1), primary retinal endothelial cells (HRECs), human umbilical vein endothelial cells (HUVECs) and human retinal pigmented epithelial cells (hRPEs). Tipranavir and teniposide were well tolerated by the mentioned retinal cells, thereby they have been further evaluated in in vitro models of glaucoma, diabetic retinopathy, and age-related macular degeneration. Tipranavir and teniposide showed retinal cell protection, modulating the expression of HIF-1α, VEGF-A, and inflammatory cytokines. Therefore, these compounds are worthy of further investigation to manage retinal degenerative conditions.","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13253766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0