Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD.
J Immunol. 2024 Sep 1;213(5):690-699. doi: 10.4049/jimmunol.2300753.
Dendritic cells (DCs) are crucial for initiating the acquired immune response to infectious diseases such as tuberculosis. Mycobacterium tuberculosis has evolved strategies to inhibit activation of the NLRP3 inflammasome in macrophages via its serine/threonine protein kinase, protein kinase F (PknF). It is not known whether this pathway is conserved in DCs. In this study, we show that the pknF deletion mutant of M. tuberculosis (MtbΔpknF) compared with wild-type M. tuberculosis-infected cells induces increased production of IL-1β and increased pyroptosis in murine bone marrow-derived DCs (BMDCs). As shown for murine macrophages, the enhanced production of IL-1β postinfection of BMDCs with MtbΔpknF is dependent on NLRP3, ASC, and caspase-1/11. In contrast to macrophages, we show that MtbΔpknF mediates RIPK3/caspase-8-dependent IL-1β production in BMDCs. Consistently, infection with MtbΔpknF results in increased activation of caspase-1 and caspase-8 in BMDCs. When compared with M. tuberculosis-infected cells, the IL-6 production by MtbΔpknF-infected cells was unchanged, indicating that the mutant does not affect the priming phase of inflammasome activation. In contrast, the activation phase was impacted because the MtbΔpknF-induced inflammasome activation in BMDCs depended on potassium efflux, chloride efflux, reactive oxygen species generation, and calcium influx. In conclusion, PknF is important for M. tuberculosis to evade NLRP3 inflammasome-mediated activation of caspase-1 and RIPK3/caspase-8 pathways in BMDCs.
树突状细胞(DCs)对于引发针对结核病等传染病的获得性免疫反应至关重要。结核分枝杆菌已经进化出通过其丝氨酸/苏氨酸蛋白激酶、蛋白激酶 F(PknF)抑制巨噬细胞中 NLRP3 炎性小体激活的策略。尚不清楚该途径是否在 DC 中保守。在这项研究中,我们表明与野生型结核分枝杆菌感染细胞相比,结核分枝杆菌 pknF 缺失突变体(MtbΔpknF)诱导小鼠骨髓来源的树突状细胞(BMDC)中 IL-1β 的产生增加和细胞焦亡增加。与鼠巨噬细胞一样,MtbΔpknF 感染 BMDC 后 IL-1β 的产生增强依赖于 NLRP3、ASC 和 caspase-1/11。与巨噬细胞相反,我们表明 MtbΔpknF 在 BMDC 中介导 RIPK3/caspase-8 依赖性 IL-1β 产生。一致地,与结核分枝杆菌感染细胞相比,MtbΔpknF 感染导致 BMDC 中 caspase-1 和 caspase-8 的激活增加。与结核分枝杆菌感染细胞相比,MtbΔpknF 感染细胞的 IL-6 产生不变,表明突变体不影响炎性小体激活的初始阶段。相反,激活阶段受到影响,因为 MtbΔpknF 在 BMDC 中诱导的炎性小体激活依赖于钾外流、氯外流、活性氧生成和钙内流。总之,PknF 对于结核分枝杆菌逃避 NLRP3 炎性小体介导的 caspase-1 和 RIPK3/caspase-8 途径在 BMDC 中的激活很重要。
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