Wnt5a Deficiency Regulates Inflammatory Cytokine Secretion, Polarization, and Apoptosis inMycobacterium tuberculosis-Infected Macrophages

Abstract

Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis (MTB), is one of the global public health catastrophes. Wnt signaling has recently been identified to exert immunoregulatory functions in a variety of inflammatory and infectious diseases, including tuberculosis. The opposite expression of Wnt5a in human and mice during MTB infection drives us to explore the roles and biological significances of reduced Wnt5a for MTB-treated mice. In our study, the reduction of WNT5A in MTB-treated mice lung tissues or MTB-infected mice bone marrow-derived macrophages (BM-Mø) was in a dose- and time-dependent manner. Then, WNT5A-silenced mice, secreted frizzled-related protein 1 (SFRP1)-overexpressed or -silenced mice BM-Mø, were constructed to regulate Wnt5a levels. When Wnt5a is deficient, MTB-induced increases of pro-inflammatory cytokines (TNF-α, IL-1β, IL-12, and IL-6) can be markedly attenuated in mice lung tissues or BM-Mø. Besides, external disturbance triggered that Wnt5a lower expression can induce Mø to be M2 phenotype and enhance cell apoptosis of MTB-infected mice BM-Mø. Hence, the reduction of Wnt5a is a tactful strategy adopted by Mø to resistant MTB-induced immune responses and to enhance MTB-induced Mø apoptosis in mice. Our study revealed a new style for Mø to manipulate themselves against MTB infection. Our research identifies that Wnt5a deficiency can regulate inflammatory cytokine secretion, polarization, and apoptosis in MTB-infected Mø.

Regulatory role and mechanism of the inhibition of the Mcl-1 pathway during apoptosis and polarization of H37Rv-infected macrophages

“…MTB infection can not only induce host macrophage apoptosis but also induce host macrophage polarization. [ 37 ] Huang et al [ 17 ] focused on the polarization of macrophages at different stages of tuberculous granuloma formation. They concluded that the polarization of macrophages was mainly M1 in the early stage of tuberculous granuloma formation, while M2-related markers gradually increased in the late stage.…”

Wnt5a is a TLR2/4-ligand that induces tolerance in human myeloid cells

“…Similarly to what we demonstrated for human myeloid cells in the current study, Toll/TLR-signalling induces the expression of WntD in the fly 28 . Further, in infection models of Wnt5a (mouse) or WntD ( D. melanogaster ) deficiency, an attenuated phenotype was observed in the former (because of reduced levels of pro-inflammatory cytokines) 37 , and in sharp contrast, an increased lethality was reported in the latter 28 . This was ascribed to the fact that the non-canonical WntD protein is a feedback inhibitor of Dorsal/NFκB-induced inflammation 28 .…”

Effect of gap junctions on RAW264.7 macrophages infected with H37Rv

“…Studies have shown that macrophages are phagocytes at the frontline of the host immune defense against MTB pathogens, [1] host macrophage apoptosis, and release of inflammatory cytokines as an important defense response to resist MTB pathogens. [3,22,23] In many cell types, GJs can transmit apoptotic signals to control the destiny of cells that are associated with the expression of Cx43. [24–26] Furthermore, researchers [10] have reported that Cx43 induces apoptosis of pancreatic cancer cells and apoptosis through the mitochondrial apoptotic pathway.…”

“…[1] When MTB encounters a host, the host macrophages trigger apoptosis and release inflammatory factors to eliminate MTB pathogens, which are the important host immune defense mechanisms. [2,3] Thus, increasing reports have explored the mechanisms between MTB and host macrophage, but the cell-mediated immune responses in host macrophages are still unclear.…”