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.
Highlights
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRR) with a crucial function in innate immune responses
We investigate global long non-coding RNA (lncRNA) expression profiles using microarray analysis of macrophages treated with LPS, and propose a model whereby TLR signaling induces the upregulation of lncRNA-Mirt[2], which serves as a repressor of inflammatory responses through interaction with tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), and inhibition of its oligomerization and auto-ubiquitination
To identify the lncRNAs that are involved in the innate immune response, we performed a microarray analysis in primary cultured peritoneal macrophages obtained from C57BL/6 mice
Summary
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRR) with a crucial function in innate immune responses. Adenovirus mediated gene transfer of Mirt[2] protects mice from endotoxemia induced fatality and multi-organ dysfunction These findings identify lncRNA Mirt[2] as a negative feedback regulator of excessive inflammation. Long non-coding RNAs (lncRNA) are a large class of nonprotein-coding transcripts that are greater than 200 bases in length[11] They are involved in many physiological and pathological processes that include genomic imprinting, embryonic development, cell differentiation, tumor metastasis and regulation of the cell cycle[12,13,14]. We investigate global lncRNA expression profiles using microarray analysis of macrophages treated with LPS, and propose a model whereby TLR signaling induces the upregulation of lncRNA-Mirt[2], which serves as a repressor of inflammatory responses through interaction with TRAF6, and inhibition of its oligomerization and auto-ubiquitination
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