Shang Feifei, Shi Xiaoke, Zeng Yao, Tao Xunqian, Li Tianzhen, Liang Yan, Yang Yanqin, Song Chuanwang
Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233030, China.
Clincial Laboratory, First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2025 Aug 20;45(8):1697-1705. doi: 10.12122/j.issn.1673-4254.2025.08.14.
To investigate the effect of avitinib for suppressing NLRP3 inflammasome activation and alleviating septic shock and explore the underlying mechanism.
Mouse bone marrow-derived macrophages (BMDM), human monocytic leukemia cell line THP-1, and peripheral blood mononuclear cells (PBMC) isolated from healthy volunteers were pre-treated with avitinib, followed by activation of the canonical NLRP3 inflammasome using agonists including nigericin, monosodium urate (MSU) crystals, or adenosine triphosphate (ATP). Non-canonical NLRP3 inflammasome activation was induced intracellular transfection of lipopolysaccharide (LPS). Western blotting was used to detect the secretory protein markers of NLRP3 inflammasome activation and assess pyroptosis, and the levels of inflammatory cytokines in cell culture supernatant were determined with ELISA. In a mouse model of LPS-induced septic shock, the effect of avitinib treatment on the levels of inflammatory cytokines in serum and peritoneal lavage fluid were examined with ELISA, and survival curves of the mice were plotted using the Kaplan-Meier method.
Avitinib significantly inhibited NLRP3 inflammasome activation in multiple cell types, and dose-dependently reduced IL-1β secretion and caspase-1 cleavage while suppressing GSDMD-mediated pyroptosis without obviously affecting IL-6 or TNF-α levels. In the mouse models of LPS-induced septic shock, avitinib significantly lowered IL-1β levels in serum and peritoneal fluid and extended survival time of the mice.
Avitinib suppresses NLRP3 inflammasome activation and alleviates septic shock in mice.
研究阿伐替尼抑制NLRP3炎性小体激活及减轻脓毒症休克的作用，并探讨其潜在机制。
用阿伐替尼预处理小鼠骨髓来源的巨噬细胞（BMDM）、人单核细胞白血病细胞系THP-1以及从健康志愿者分离的外周血单核细胞（PBMC），随后使用尼日利亚菌素、尿酸单钠（MSU）晶体或三磷酸腺苷（ATP）等激动剂激活经典NLRP3炎性小体。通过细胞内转染脂多糖（LPS）诱导非经典NLRP3炎性小体激活。采用蛋白质免疫印迹法检测NLRP3炎性小体激活的分泌蛋白标志物并评估细胞焦亡，用酶联免疫吸附测定法（ELISA）测定细胞培养上清液中炎性细胞因子的水平。在脂多糖诱导的脓毒症休克小鼠模型中，用ELISA检测阿伐替尼治疗对血清和腹腔灌洗液中炎性细胞因子水平的影响，并用Kaplan-Meier法绘制小鼠生存曲线。
阿伐替尼显著抑制多种细胞类型中NLRP3炎性小体的激活，并剂量依赖性地减少白细胞介素-1β（IL-1β）分泌和半胱天冬酶-1（caspase-1）裂解，同时抑制Gasdermin D（GSDMD）介导的细胞焦亡，而不明显影响IL-6或肿瘤坏死因子-α（TNF-α）水平。在脂多糖诱导的脓毒症休克小鼠模型中，阿伐替尼显著降低血清和腹腔液中IL-1β水平，并延长小鼠存活时间。
阿伐替尼可抑制小鼠NLRP3炎性小体激活并减轻脓毒症休克。
