IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling
IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling
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DOI：
10.4049/jimmunol.1900169
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发表时间：
2019-08-15
影响因子：
4.4
通讯作者：
Ma, Li
中科院分区：
文献类型：
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作者：
Gao, Yuchi;Wen, Qian;Ma, Li
结核分枝杆菌主要感染单核吞噬细胞，仍然是全世界人类细菌感染导致巨大发病率和死亡率的主要原因。 IL-1 细胞因子家族对于宿主对结核分枝杆菌的抵抗力至关重要。作为IL-1家族中新发现的一个亚类，虽然IL-36细胞因子已被证明在预防结核分枝杆菌感染方面发挥作用，但其抗菌机制仍知之甚少。在这项研究中，我们证明 IL-36 γ 通过激活自噬以及诱导 WNT5A（据报道是涉及多种炎症性疾病的 IL-1 下游效应子）赋予人单核细胞源性巨噬细胞细菌耐药性。进一步的研究表明，WNT5A 可以通过诱导环氧合酶-2 (COX-2) 表达来增强单核细胞来源的巨噬细胞的自噬，进而通过非经典 WNT 信号传导降低 AKT/mTOR 的磷酸化。一致地，IL-36 γ 功能的潜在分子机制也是由 COX-2/AKT/mTOR 信号轴介导的。总而言之，我们的研究结果揭示了 IL-36 γ 作为自噬诱导剂的新活性，它代表了控制人类巨噬细胞中结核分枝杆菌感染结果的关键炎症细胞因子。
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-36 gamma 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-36 gamma function are also mediated by the COX-2/AKT/mTOR signaling axis. Altogether, our findings reveal a novel activity for IL-36 gamma as an inducer of autophagy, which represents a critical inflammatory cytokine that control the outcome of M. tuberculosis infection in human macrophages.