Role of miR-155 and miR-146a in Mast Cell Function

Mast cells are resident immune cells abundantly found in the tissue at the host-environment interface, where they play a critical role in inflammatory allergic responses. Mast cell responses may be regulated by the cytokine milieu at the site of inflammation. Recent studies have revealed microRNAs to be important in altering cytokine signaling in immune cells. Here, we demonstrate for the first time that IL-10 and IL-33 induce miR-155 and miR-146a, respectively, to alter mast cell functions. We report that IL-10 enhanced IgE induced activation of mast cells. IL-10 effects are dependent on Stat3 activation, which elicits miR-155 expression, resulting in a loss of suppressor of cytokine signaling-1 (SOCS-1). The importance of miR-155 was demonstrated by the inability of IL-10 to enhance anaphylaxis in miR-155–deficient mice. Additionally, we show that IL-33 treatment greatly enhances miR-146a expression in mast cells and in mast cell derived exosomes. miR-146a induction is dependent on MyD88 and NFκB and seems to negatively regulate ST2 signaling, which is demonstrated by the hyperresponsiveness of miR-146a knockout BMMC in response to IL-33. Our preliminary data suggest that miR-146a serves as a feedback negative regulator of IL-33 signaling by targeting IRAK proteins. miR-155 and miR-146a are key microRNAs that regulate a range of immune functions. Taken together, our results reveal two novel microRNA pathways that regulate mast cell IgE and IL-33 induced responses