NLRP3-activated bone marrow dendritic cells play antileukemic roles via IL-1β/Th1/IFN-γ in acute myeloid leukemia
NLRP3-activated bone marrow dendritic cells play antileukemic roles via IL-1β/Th1/IFN-γ in acute myeloid leukemia
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NLRP3 激活的骨髓树突状细胞通过 IL-1β/Th1/IFN-γ 在急性髓系白血病中发挥抗白血病作用
DOI：
10.1016/j.canlet.2021.06.014
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发表时间：
2021
期刊：
影响因子：
9.7
通讯作者：
Daoxin Ma
中科院分区：
文献类型：
--
作者：
Qinqin Liu;Mingqiang Hua;Chen Zhang;Ruiqing Wang;Jinting Liu;Xinyu Yang;Fengjiao Han;Ming Hou;Daoxin Ma
急性髓系白血病(AML)以免疫抑制为特征的骨髓微环境促进了白血病的免疫逃逸。阐明免疫抑制机制和开发有效的免疫治疗策略是必要的。在此，我们发现急性髓系白血病患者骨髓中Th1%和干扰素-γ水平下调，NLRP3激活的BMDCs通过分泌IL-1β促进CD_4~+T细胞向Th1细胞分化。然而，NLRP3激活的BMDCs在NLRP3炎症体抑制剂MCC950或抗IL-1γ抗体的存在下，不能在体外诱导产生干扰素-β的Th1细胞，除非补充外源性IL-1β。在Nlrp3-/-小鼠和抗IL-1β抗体处理的小鼠中也观察到了这种对Th1分化的抑制作用。值得注意的是，在体外和体内，Th1细胞水平的升高通过分泌干扰素-γ促进了白血病细胞的凋亡和抑制了其增殖。因此，NLRP3激活的BMDCs促进产生干扰素γ的Th1细胞的增殖，具有抗白血病的作用，并可能为急性髓细胞白血病患者的白血病免疫治疗提供基础。
The bone marrow microenvironment of acute myeloid leukemia (AML) characterized by immunosuppressive features fosters leukemia immune escape. Elucidating the immunosuppressive mechanism and developing effective immunotherapeutic strategies are necessary. Here, we found that the Th1% and IFN-γ level were downregulated in bone marrow of AML and NLRP3-activated BMDCs promoted CD4+ T cell differentiation into Th1 cells via IL-1β secretion. However, IFN-γ-producing Th1 cells were not induced by NLRP3-activated BMDCs in the presence of the NLRP3 inflammasome inhibitor MCC950 or anti-IL-1β antibody in vitro unless exogenous IL-1β was replenished. This inhibitory effect on Th1 differentiation was also observed in Nlrp3-/- mice or anti-IL-1β antibody-treated mice. Notably, elevated Th1 cell levels promoted apoptosis and inhibited proliferation in leukemia cells via IFN-γ secretion in vitro and in vivo. Thus, NLRP3-activated BMDCs promote the proliferation of IFN-γ-producing Th1 cells with antileukemic effects and may provide insight into the basis for leukemia immunotherapy in patients with AML.