Journal
JOURNAL OF IMMUNOLOGY
Volume 203, Issue 4, Pages 922-935Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1900169
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Funding
- National Science and Technology Major Project [2017ZX10201301-008]
- National Natural Science Foundation of China [81772150, 81571951]
- Guangdong Natural Science Foundation [2016A030311001]
- Science and Technology Project of Guangdong Province [2017A020212007]
- Science and Technology Project of Guangzhou [201707010215]
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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.
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