MicroRNA-302b is a new regulator of inflammatory responses via feedback to TLR/IRAK4 circuits during bacterial infection (INM9P.459)

Abstract MicroRNAs (miRNAs) have been implicated in a spectrum of physiological and pathological conditions, including immune responses. miR-302b has been implicated in stem cell differentiation and cell proliferation; however its role in infection and immunity remains to be defined. In this study, we showed that miR-302b was induced by TLR2 and TLR4 through ERK-p38- NF-κB signaling upon Gram-negative bacterium Pseudomonas aeruginosa infection. Suppression of inflammatory responses to bacterial infection is mediated by targeting IRAK4, a protein required for the activation and nuclear translocation of NF-κB. Through negative feedback, enforced expression of miR-302b in mice with its “mimics” (or IRAK4 siRNA silencing) inhibited downstream NF-κB signaling and airway leukocyte infiltration, thereby alleviating lung injury and increasing survival in P. aeruginosa-infected mice. Similarly, IRAK4 siRNA silencing blocked airway leukocyte infiltration and inflammatory cytokine production, thereby increasing survival after infection in mice. On the other hand, miR-302b inhibitors exacerbated inflammatory responses and decreased survival in both P. aeruginosa-infected mice and lung epithelial and macrophage cells. Collectively, our findings revealed that miR-302b is a novel inflammatory regulator of NF-κB activation in respiratory bacterial infections through negative feedback to TLRs-mediated immunity.