IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

作者：Yuchi Gao, Qian Wen, Shengfeng Hu, Xinying Zhou, Wenjing Xiong, Xialin Du, Lijie Zhang, Yuling Fu, Jiahui Yang, Chaoying Zhou, Zelin Zhang, Yanfen Li, Honglin Liu, Yulan Huang, Li Ma · 发表于：The Journal of Immunology · 年份：2019 · DOI：10.4049/jimmunol.1900169 · 被引用次数：45 · 研究领域：Immune Cell Function and Interaction、Toxin Mechanisms and Immunotoxins、Autophagy in Disease and Therapy

Abstract Mycobacterium tuberculosis, which primarily infects mononuclear phagocytes, remains the leading bacterial cause of enormous morbidity and mortality because of bacterial infections in humans throughout the world. The IL-1 family of cytokines is critical for host resistance to M. tuberculosis. As a newly discovered subgroup of the IL-1 family, although IL-36 cytokines have been proven to play roles in protection against M. tuberculosis infection, the antibacterial mechanisms are poorly understood. In this study, we demonstrated that IL-36γ conferred to human monocyte-derived macrophages bacterial resistance through activation of autophagy as well as induction of WNT5A, a reported downstream effector of IL-1 involved in several inflammatory diseases. Further studies showed that WNT5A could enhance autophagy of monocyte-derived macrophages by inducing cyclooxygenase-2 (COX-2) expression and in turn decrease phosphorylation of AKT/mTOR via noncanonical WNT signaling. Consistently, the underlying molecular mechanisms of IL-36γ function are also mediated by the COX-2/AKT/mTOR signaling axis. Altogether, our findings reveal a novel activity for IL-36γ as an inducer of autophagy, which represents a critical inflammatory cytokine that control the outcome of M. tuberculosis infection in human macrophages.