Abstract
Apoptosis of alveolar macrophages following Mycobacterium tuberculosis infection have been demonstrated to play a central role in the pathogenesis of tuberculosis. In the present study, we found that Wnt/β-catenin signaling possesses the potential to promote macrophage apoptosis in response to mycobacterial infection. In agreement with other findings, an activation Wnt/β-catenin signaling was observed in murine macrophage RAW264.7 cells upon Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection at a multiple-of-infection of 10, which was accompanied with up-regulation of pro-inflammatory cytokines TNF-α and IL-6 production. However, the BCG-induced TNF-α and IL-6 secretion could be significantly reduced when the cells were exposed to a canonical Wnt signaling ligand, Wnt3a. Importantly, the activation of Wnt/β-catenin signaling was able to further promote apoptosis in BCG-infected RAW264.7 cells in part by a mitochondria-dependent apoptosis pathway. Immunoblotting analysis further demonstrated that Wnt/β-catenin signaling-induced cell apoptosis partly through a caspase-dependent apoptosis mechanism by down-regulation of anti-apoptotic protein Mcl-1, and up-regulation of pro-apoptotic proteins Bax and cleaved-caspase-3, as well as enhancement of caspase-3 activity in BCG-infected RAW264.7 cells. These data may imply an underlying mechanism of alveolar macrophages in response to mycobacterial infection, by which the pathogen induces Wnt/β-catenin signaling activation, which in turn represses mycobacterium-trigged inflammatory responses and promotes mycobacteria-infected cell apoptosis.
Highlights
The infection of Mycobacterium tuberculosis (Mtb) is the cause of tuberculosis (TB), which remains a major public health problem in most parts of the world, in developing countries.Despite intensive efforts aimed to understand the underlying mechanism of the interactions of Mtb and host cells, including the alveolar macrophages, our knowledge of the nature between a protective and a pathological host response of Mtb infection is limited [1]
Bacillus Calmette-Guerin (BCG) Activated Canonical Wnt Signaling in Macrophage RAW264.7 Cells
It has been demonstrated that the mode of cell death of macrophages following Mtb infection play a central role in the pathogenesis of TB, in which the apoptotic death of the infected cells is likely associated with the elimination of Mtb, while necrotic cell death may facilitate the dissemination and transmission of pathogens [5,7]
Summary
Despite intensive efforts aimed to understand the underlying mechanism of the interactions of Mtb and host cells, including the alveolar macrophages, our knowledge of the nature between a protective and a pathological host response of Mtb infection is limited [1]. It has been proven that the cell death (apoptotic cell death and necrotic cell death) of macrophage following Mtb infection plays a central role in the pathogenesis of TB. In this context, Mtb infection induces pro-inflammatory cytokines and chemokines, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), by which the TNF-α is capable of subsequently inducing macrophages to produce other cytokines and chemokines, which in turn modulates macrophage apoptosis and necrosis [3]
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