ROLE OF MICRORNA IN MACROPHAGE POLARIZED ACTIVATION

Macrophages are cells from the innate branch of immune system with central roles both under physiologic and pathologic conditions. Such complex behaviour relies on extreme functional plasticity of these cells. Cellular activation and plasticity in macrophages are complex phenomena that require tight regulation. In recent years, microRNAs and lncRNAs emerged as important regulators of many cellular processes and have been proposed as key mediators of the plasticity observed in macrophages. In this study we investigate the possible roles of different microRNAs on macrophage activation and functionality, taking advantage of animal models selectively depleted of candidate miRNA in macrophages. We found that selective depletion of miR-125a in macrophages did not affect clinical outcome in different in vivo models of inflammation. Nonetheless it altered macrophage activation and functions, as evidenced by reduced secretion of TNFα after endotoxin challenges. Consistently, macrophages deficient in miR-125a displayed reduced killing of extracellular bacteria although they showed increased phagocytic rate as compared to miR-125a competent cells. With a similar approach, we confirmed that miR-9 is induced in macrophages upon inflammatory stimuli. Increased expression of miR-9 mature form in mice was sustained by the synchronous activation of transcription in both pri-miR-9.1 and pri-miR-9.3 loci, in contrast to human. Finally we identified a lncRNA interfering with the processing of a pro-inflammatory miRNA in differentially activated human macrophages, highlighting a new layer of regulation of macrophage activation. The finding of the present project give new insights into the complex mechanism regulating macrophage activation and underscores the need for future studies to thoroughly identify the molecular mechanisms and the involvement of different miRNA in macrophage activation. Moreover, such studies could set the basis for the transition from basic research to new therapeutic options enabling precise regulation of macrophages activation in different immune pathologies.