Levels of miR-125a-5p are altered in Mycobacterium avium-infected macrophages and associate with the triggering of an autophagic response

Abstract

Macrophages are major pathogen-killing cells. Mycobacteria can represent a serious threat to human health, in particular Mycobacterium tuberculosis and, less so, the opportunistic Mycobacterium avium. They can cause disseminated infections because of their capacity to survive and proliferate within macrophage phagolysosomes. Accumulating evidence indicates that the regulation of miRNA expression is implicated in the mechanisms of defense of macrophages against mycobacterial infections. Nevertheless, the precise contribution of miRNAs is largely unknown. The present study analyzes the expression profile of miRNAs during M. avium infection of macrophages by means of microarrays. We detected that the levels of 23 miRNAs were significantly changed ≥2.5-fold 24 h after M. avium infection. In particular, MiR-125a-5p was found to be highly expressed as part of the known immunological response of macrophages to bacterial or viral infections. MiR-125a-5p overexpression inhibited the expression of target signal transducers and activators of transcription 3 (STAT3) in THP-1 cells. Conversely, inhibitors of miR-125a-5p had the opposite effect. Silencing of STAT3 significantly enhanced the level of autophagy in both uninfected and M. avium-infected cells. Overexpression of miR-125a-5p significantly increased autophagy and decreased M. avium survival within THP-1 cells. Instead, co-transfection with miR-125a-5p mimic and a human STAT3 expressing construct reversed the effects: autophagy decreased and intracellular bactericidal survival was improved. Taken together, our findings indicate that miR-125a-5p participates in the regulation of innate host defenses by targeting STAT3 and enhancing autophagy levels. The results reported here contribute to a better understanding of host defense mechanisms against mycobacterial infections and offer some clues about their control.

Keywords: Autophagy; Macrophage; MiR-125a-5p; Mycobacterium avium; STAT3.