miR-146a is critical for orchestrating Mycobacterium fortuitum survival through anti-inflammatory and M2 macrophage responses in fish.

The significance of microRNAs (miRNAs) in host response to non-tuberculoid mycobacteria like Mycobacterium fortuitum remains nascent. Using zebrafish kidney macrophages (ZFKM), we elucidate a novel function of miR-146a, orchestrated by the TLR-2-PI3K-NF-κB pathway, in M. fortuitum pathogenesis. We demonstrate that miR-146a facilitates anti-inflammatory response by targeting IRAK-1 and TRAF-6 in M. fortuitum-infected ZFKM. Moreover, miR-146a mitigates M1 macrophage activity by suppressing the iNOS-NO axis while enhancing M2-specific TGF-β mRNA expression and subsequent inhibition of M. fortuitum eradication. These findings collectively suggest that miR-146a diminishes macrophage-mediate M. fortuitum clearance. Our study provides novel insights into the intricate interplay between miRNAs and mycobacterial infections. We propose a mechanistic model wherein the TLR-2/NF-κB axis initiates miR-146a expression, which, in turn, suppresses irak-1 and traf-6, fostering the development of M2 macrophages. Consequently, this creates an anti-inflammatory environment conducive to M. fortuitumsurvival. Our findings provide novel insights into the intricate interplay between miRNAs and mycobacterial persistence, a concerning aspect of pathogenesis.