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

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.

High Expression of IL-36γ in Influenza Patients Regulates Interferon Signaling Pathway and Causes Programmed Cell Death During Influenza Virus Infection

“…Furthermore, we observed that IL-36g could effectively regulate interferon-related signaling pathway and control the progress of PCD via promoting apoptosis and inhibiting autophagy in the early stages of infection, suggesting its auxiliary role in innate immunity to influenza infection. It has been reported that IL-36g or IL-36a significantly upregulated in patients with active pulmonary tuberculosis and bacterial pneumonia (11,24). In our study, we observed higher concentrations of IL-36g in plasma and elevated mRNA levels of IL-36G and IL-36R in influenza-induced ARDS patients, suggesting its potential association with viral infection.…”

Functions of the WNT Signaling Network in Shaping Host Responses to Infection

“…A recent study suggested that in human monocyte-derived macrophages infected with M. tuberculosis , WNT5A contributed to enhancing autophagy resulting in a small decrease in intracellular bacterial burden. In this study, WNT5A-mediated autophagy was suggested as an effector mechanism of IL-36γ (102). However, as WNT5A expression in human macrophages is rapidly induced by M. tuberculosis infection (34), this mechanism might represent an amplification of the WNT5A response of these cells as indicated for other cytokines such as TNF (19).…”

“…These observations further suggest a role for Wnt5a, and potentially other WNT ligands in host cell uptake of P. aeruginosa . However, treatment of RAW264.7 cells with recombinant Wnt5a did not alter internalization of L. donovani (80), and siRNA-mediated knock-down of endogenous WNT5A did not impair phagocytosis of M. tuberculosis by human monocyte-derived macrophages (102). Thus, the effects of WNT5A on phagocytosis of bacterial pathogens requires further investigation, including comparisons of extracellular alongside intracellular pathogens and macrophages of different origins.…”

Role of Wnt5a in periodontal tissue development, maintenance, and periodontitis: Implications for periodontal regeneration (Review)

“…Wnt5a induced the expression of anti-inflammatory mediator IL-10 in primary human monocytes ( 53 ), and promoted macrophage M2 polarization in kidney fibrosis ( 54 ). In addition, Wnt5a was found to have an important role in killing Mycobacterium tuberculosis by enhancing autophagy of human monocyte-derived macrophages ( 55 ). Thus, the specific role of Wnt5a in inflammation remains inconclusive, and it may depend on the tissue-specific immune microenvironment or the stage of immune response.…”