Upregulation of miR-146a-5p and miR-146b-5p limits IL-1β-mediated signaling in adipose tissue during polytrauma by downregulating IRAK1.

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs and play a crucial role in the regulation of inflammation. White adipose tissue (WAT) covers the body and internal organs in subcutaneous and visceral fat depots, respectively, and represents an important source of circulating miRNAs. The role of WAT and its miRNAs in the context of polytrauma is incompletely understood. However, evidence is accumulating that WAT contributes to the severe inflammatory response observed in polytrauma patients. Therefore, we analyzed the miRNA expression in inguinal WAT depots in a standardized mouse model of polytrauma and hemorrhagic shock (PT+HS). Here, we identified miR-146a-5p and miR-146b-5p to be upregulated upon PT+HS. In anmodel of human white adipocytes, we found miR-146a-5p to be upregulated by IL-1β-induced NF-κB activation. Both, miR-146a-5p and miR-146b-5p, in turn, dampened IL-1β-induced inflammation in human adipocytes. Using target gene prediction tools, we further confirmed IRAK1 as target of miR-146a-5p, and potentially also miR-146b-5p, underlining the importance of IRAK1 in IL-1β-induced proinflammatory signaling. Thus, miR-146a-5p and miR-146b-5p act as suppressors of IL-1β-induced proinflammatory signaling in human adipocytes during trauma, and blockage of IL-1β or mimics of miR-146a-5p and miR-146b-5p might represent a potential future therapeutic avenue for severe traumatic and inflammatory conditions.