The LPS-inducible lncRNA Mirt2 is a negative 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.

Lipopolysaccharide‐induced DNA damage response activates nuclear factor κB signalling pathway via GATA4 in dental pulp cells

“…LPS stimulation can result in the induction of NF-jB, p38, JNK, MAPK, IRF3 and IFNb through the TLR4-MyD88-IRAKs-TRAF6-dependent or the TLR4-TRIF-TRAF3-IRF3-dependent pathway (Palsson-McDermott & O'Neill 2004, Du et al 2017). After recognizing LPS, TLR4 recruits specific adaptor proteins, including MyD88 and TRIF, and sequentially stimulates multiple signalling pathways to induce target gene expression.…”

Long non‐coding RNA expressed in macrophage co‐varies with the inflammatory phenotype during macrophage development and polarization

“…LPS induced up‐regulation of lncRNA Mirt2 in the cytoplasm, but the increase in Mirt2 was restricted by sustained and excessive activation of inflammatory responses at the late stage. Restoring Mirt2 expression in later stage promoted the IL‐4 induced M2 polarization with a remarkable increased level of M2 markers . HOTTIP expression was associated with TLR tolerance, and has been speculated to skew macrophage polarization to a “M2‐like” phenotype .…”

“…Functionally, M1‐type macrophage promotes Th1 response and produces copious amounts of pro‐inflammatory cytokines or reactive oxygen species (ROS) to kill pathogens . TLR‐triggered NF‐κB is one of the best studied pathways participated in the conversion of macrophage to M1‐like phenotype, which is shown in Figure . All TLRs, excluding TLR3, mainly activate the NF‐κB‐dependent or IRF7‐dependent type I IFN (TLR7‐9) pro‐inflammatory signallings via the adapter protein myeloid differentiation marker 88 (MyD88) .…”

“…Then TAK1 activates the inhibitor of κB α (IκBα) kinases (IKKs), leading to degradation of IκBα and activation of NF‐κB, immune and inflammatory responses. LncRNAs promote the development of M1 macrophage via NF‐κB or other pathways showed in red font, whereas negative regulated displayed in blue font…”

“…After restoring the expression of Mirt2, IL‐4 treated macrophage was inclined to M2 polarization with a high level of M2 molecule markers. However, the elaborate mechanisms of macrophage polarization induced by Mirt2 are still unknown . Murphy et al conducted real‐time PCR in LPS‐tolerized macrophage and found increased expression of lncRNA HAR1A and HAR1B but decreased levels of PCGEM1 and HOTTIP lncRNAs .…”