Caspase-1依赖的细胞焦亡在HIV-1感染导致pDCs损耗中的作用研究

The role of Caspase-1 dependent pyroptosis in plasmacytoid dendritic cells depletion caused by HIV-1 infection

目的:探讨Caspase-1依赖的细胞焦亡在人类免疫缺陷病毒1型(HIV-1)感染者外周血浆细胞样树突状细胞(pDCs)损耗中的作用机制。方法:比较HIV-1感染者与健康志愿者外周血pDCs细胞频率和细胞焦亡水平。体外诱导分化人单核细胞白血病细胞THP1来源的树突状细胞(DCs)(THP1-DCs),分为阴性对照组、HIV-1感染组、阴性对照+HMGB1抑制剂甘草酸组和HIV-1感染+甘草酸组。检测HIV-1感染或不感染THP1-DCs的细胞焦亡、HMGB1释放、Caspase-1/GSDMD信号轴激活水平。结果:HIV-1感染者外周血单个核细胞(PBMCs)中pDCs细胞频率显著低于健康志愿者(P=0.001)。HIV-1感染者pDCs细胞焦亡水平以及Caspase-1、GSDMD、白介素(IL)-1β、HMGB1 mRNA表达水平升高(P<0.05)。与阴性对照组比较,HIV-1感染组THP1-DCs的HMGB1、Caspase-1、GSDMD以及IL-1β和IL-18表达水平升高(P<0.05);与HIV-1感染组比较,HIV-1感染+甘草酸组细胞焦亡以及Caspase-1、GSDMD、IL-1β和IL-18 mRNA和(或)蛋白表达水平降低(P<0.05)。结论:HIV-1感染可通过激活Caspase-1/GSDMD信号轴,释放IL-1β和IL-18等炎症因子,诱发pDCs细胞焦亡,可能是HIV-1感染者外周血pDCs细胞损耗的重要原因。

Objective:To explore the mechanism of Caspase-1 dependent pyroptosis in the peripheral blood plasmacytoid dendritic cells(pDCs)depletion in patients infected with human immunodeficiency virus type 1(HIV-1).Methods:The frequency of pDCs cells in peripheral blood of HIV-1 infected and healthy volunteers and the level of pyroptosis were compared.Induced differentiation of dendritic cells(DCs)derived from human monocytic leukemia cells THP1(THP1-DCs)in vitro were divided into negative control group,HIV-1 infection group,negative control+HMGB1 inhibitor glycyrrhizic acid group and HIV-1 infection+glycyrrhizic acid group.Pyroptosis,release of HMGB1,and activation of Caspase-1/GSDMD signal axis were detected in HIV-1 infected and non-infected THP1-DCs cells.Results:The frequency of pDCs in peripheral blood mononuclear cells(PBMCs)of HIV-1 patients was significantly lower than that of healthy volunteers(P=0.001).The pyroptosis level and mRNA expressions of Caspase-1,GSDMD,interleukin(IL)1βand HMGB1 increased in HIV-infected pDCs(P<0.05).Compared with the negative control group,the expressions of HMGB1,Caspase-1,GSDMD,IL-1βand IL-18 of THP1-DCs in HIV-1 infection group increased(P<0.05);compared with HIV-1 infection group,pyroptosis and mRNA and/or protein expressions of Caspase-1,GSDMD,IL-1βand IL-18 in HIV-1+glycyrrheic acid group decreased(P<0.05).Conclusions:HIV-1 infection can induce pyroptosis of pDCs cells by activating the Caspase-1/GSDMD signaling axis,and releasing IL-1β,IL-18 and other inflammatory factors,which may be an important reason for pDCs depletion in peripheral blood of HIV-1 infected patients.