Circulating microRNAs Trigger Innate Immune Activation in Polytraumatic Injury

Abstract

Inflammatory responses frequently follow severe traumatic injury and are, in part, a consequence of innate immune activation by endogenous immune triggers such as extracellular and micro-(mi)RNAs recognized by the pattern recognition receptor Toll-like receptor 7 (TLR7). However, excessive immune responses may lead to inappropriate systemic inflammation that contributes to multiple organ failure. Here, we developed a novel mouse model of polytraumatic injury and evaluated the circulating plasma RNAs and miRNAs. We report that polytrauma causes significant elevations in plasma miRNA with distinct patterns of up- and down-regulation of host plasma small miRNAs. Next, we tested the pro-inflammatory function of miRNAs in bone marrow-derived macrophage culture and in a murine air pouch model of inflammation. We found that miRNAs with high uridine (U) contents >40% released into circulation induce a robust TLR7-dependent inflammatory response, revealing a pivotal role of circulating U-rich miRNAs as a key damage-associated molecular pattern (DAMP) in polytrauma.