The LPS-inducible lncRNA Mirt2 is a negative regulator of inflammation

TLDR

Toll‑like receptors are pattern‑recognition receptors that initiate innate immune responses, and LPS activation of TLR4 triggers proinflammatory signaling through the E3 ubiquitin ligase TRAF6. This study demonstrates that the LPS‑induced lncRNA Mirt2 acts as a checkpoint to curb excessive inflammation and may regulate macrophage polarization. Mirt2 binds TRAF6 and reduces its Lys63‑linked ubiquitination, thereby inhibiting NF‑κB and MAPK pathways and limiting proinflammatory cytokine production. Adenoviral delivery of Mirt2 protects mice from endotoxemia‑induced fatality and organ dysfunction, establishing Mirt2 as a negative feedback regulator of inflammation.

Abstract

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRR) with a crucial function in innate immune responses. Activation of TLR4 signaling at the plasma membrane by lipopolysaccharide (LPS) stimulates proinflammatory signaling pathways dependent on the E3 ubiquitin ligase TRAF6. Here we show the LPS-induced long non-coding RNA (lncRNA) Mirt2 functions as a checkpoint to prevent aberrant activation of inflammation, and is a potential regulator of macrophage polarization. Mirt2 associates with, and attenuates Lys63 (K63)-linked ubiquitination of, TRAF6, thus inhibiting activation of NF-κB and MAPK pathways and limiting production of proinflammatory cytokines. Adenovirus mediated gene transfer of Mirt2 protects mice from endotoxemia induced fatality and multi-organ dysfunction. These findings identify lncRNA Mirt2 as a negative feedback regulator of excessive inflammation.