MiR-155-Induced Activation of Pro-Inflammatory Stat1/TBX21 Pathway and M1-Signature Genes Incite Macrophage Apoptosis and Clearance of Mycobacterium fortuitum in Zebrafish

Abstract

The role of microRNAs (miRNAs) in Mycobacterium fortuitum pathogenesis is not well illustrated. Using zebrafish kidney macrophages (ZFKM) we observed that M. fortuitum triggers miR-155 expression, and the TLR-2/NF-κB axis plays a key role in initiating the process. We report that mir-155 activates the pro-inflammatory Stat1/TBX21 pathway in M. fortuitum-infected ZFKM. Our results further reveal the role of miR-155 in M1-macrophage polarisation during M. fortuitum infection. We observed that miR-155 inhibits socs1 expression augmenting the expression of tnf-α, il-12 and ifn-γ in infected ZFKM. Additionally, attenuating miR-155 inhibited ZFKM apoptosis and increased the intracellular bacterial load implicating its pro-apoptotic and bactericidal role in M. fortuitum pathogenesis. This is the first report on the role of miRNA in regulating innate immunity to mycobacteria in fish. We propose that the TLR-2/NF-κB axis triggers miR-155 expression, which in turn represses socs1 and promotes the development of M1-macrophages. Thus, the functional miR-155/Stat1/TBX21pathway induces a pro-inflammatory milieu favouring ZFKM apoptosis and M. fortuitum clearance. Therefore, our study unveils the role of miR-155 in the hierarchy of events leading to M. fortuitum-induced apoptosis and bacterial clearance in fish that is still not explored in detail.