Intelligent Mechanisms of Macrophage Apoptosis Subversion by Mycobacterium

Abstract

Macrophages are one of the first innate defense barriers and play an indispensable role in communication between innate and adaptive immune responses, leading to restricted Mycobacterium tuberculosis (Mtb) infection. The macrophages can undergo programmed cell death (apoptosis), which is a crucial step to limit the intracellular growth of bacilli by liberating them into extracellular milieu in the form of apoptotic bodies. These bodies can be taken up by the macrophages for the further degradation of bacilli or by the dendritic cells, thereby leading to the activation of T lymphocytes. However, Mtb has the ability to interplay with complex signaling networks to subvert macrophage apoptosis. Here, we describe the intelligent strategies of Mtb inhibition of macrophages apoptosis. This review provides a platform for the future study of unrevealed Mtb anti-apoptotic mechanisms and the design of therapeutic interventions.

Keywords: Keywords Mycobacterium; apoptosis; cytokine; effector; macrophage; microRNA.

Figure 1

Mycobacterium evades macrophage apoptosis by induction of anti-apoptotic cytokines and miRNAs expression. Three cytokines, namely, IL-10, IL-17A, and EBI3, were demonstrated to play an anti-apoptotic role during Mtb infection. IL-10 can mediate the expression of anti-apoptotic Bcl2 and Bcl3 protein and suppresses the production of pro-apoptotic factors, including TNF-α, nitric oxide (NO), and P53. IL-17A signaling leads to suppression of P53 mediated Bax mitochondrial translocation. EBI3 can directly inhibit caspase-8 and caspase-3 activation. Nine anti-apoptotic miRs were found selectively regulated by Mtb. Has-let-7b-5p can target Fas leading to inhibition of downstream activation of caspase-3. Let-7a and miR-29a are targeting caspase-3 and caspase-7, respectively. MiR-155 can abolish expression of SH2 domain-containing inositol 5-phosphatase 1(SHIP1), leading to activation of phosphatidylinositol 3-kinase (PI3K) signaling-mediated inhibition of pro-apoptotic factors including Bad, FOXO-1 and 3. In addition, miR-155 can directly targeting and suppressing the expression of FOXO-3. MiR-582-5p can target the mRNA of FOXO-1 and block its expression. MiR-20a-5p can abrogate the activation of pro-apoptotic factor Bim by targeting the JNK-2 signaling pathway. However, miR-20b-5p can enhance the expression of anti-apoptotic factor Mcl-1, which can mediate block Bax mitochondrial translocation. The role of miR-21 in regulating anti-apoptotic Bcl-2 remains controversial.