Vervaeke Alex, Lamkanfi Mohamed
Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.
Immunol Rev. 2025 Jan;329(1):e13436. doi: 10.1111/imr.13436.
Inflammasomes are crucial mediators of both antimicrobial host defense and inflammatory pathology, requiring stringent regulation at multiple levels. This review explores the pivotal role of mitogen-activated protein kinase (MAPK) signaling in modulating inflammasome activation through various regulatory mechanisms. We detail recent advances in understanding MAPK-mediated regulation of NLRP3 inflammasome priming, licensing and activation, with emphasis on MAPK-induced activator protein-1 (AP-1) signaling in NLRP3 priming, ERK1 and JNK in NLRP3 licensing, and TAK1 in connecting death receptor signaling to NLRP3 inflammasome activation. Furthermore, we discuss novel insights into MAPK signaling in human NLRP1 inflammasome activation, focusing on the MAP3K member ZAKα as a key kinase linking ribosomal stress to inflammasome activation. Lastly, we review recent work elucidating how Bacillus anthracis lethal toxin (LeTx) manipulates host MAPK signaling to induce macrophage apoptosis as an immune evasion strategy, and the counteraction of this effect through genotype-specific Nlrp1b inflammasome activation in certain rodent strains.
炎性小体是抗微生物宿主防御和炎症病理学的关键介质，需要在多个层面进行严格调控。本综述探讨了丝裂原活化蛋白激酶（MAPK）信号通路通过各种调控机制在调节炎性小体激活中的关键作用。我们详细阐述了在理解MAPK介导的NLRP3炎性小体启动、许可和激活调控方面的最新进展，重点关注MAPK诱导的激活蛋白-1（AP-1）信号通路在NLRP3启动中的作用、ERK1和JNK在NLRP3许可中的作用，以及TAK1在将死亡受体信号与NLRP3炎性小体激活相连接中的作用。此外，我们讨论了关于人类NLRP1炎性小体激活中MAPK信号通路的新见解，重点关注MAP3K成员ZAKα作为连接核糖体应激与炎性小体激活的关键激酶。最后，我们回顾了最近的研究工作，这些工作阐明了炭疽杆菌致死毒素（LeTx）如何操纵宿主MAPK信号通路以诱导巨噬细胞凋亡作为一种免疫逃避策略，以及某些啮齿动物品系中通过基因型特异性Nlrp1b炎性小体激活对这种效应的抵消作用。
