Epigenetically modulated LRRC33 acts as a negative physiological regulator for multiple Toll-like receptors.

Journal of leukocyte biology

PubMedID: 24550525

Su X, Mei S, Liang X, Wang S, Liu J, Zhang Y, Bao Y, Chen Y, Che Y, Chunhua Zhao R, Zhang Z, Yang R. Epigenetically modulated LRRC33 acts as a negative physiological regulator for multiple Toll-like receptors. J Leukoc Biol. 2014;.
The members of a LRR family play crucial roles in the activation of innate and adaptive immune responses. We reported previously that LRRC33, a transmembrane protein of the LRR family, might potentially affect TLR-mediated activity. Here, we demonstrate that LRRC33 is a negative physiological regulator for multiple TLRs. Lrrc33(-/-) and Lrrc33(+/)(-) mice were more susceptible to TLR ligand challenges. The macrophages and DCs from Lrrc33(-)(/)(-) mice produced more proinflammatory cytokines than those of WT mice through increased activation of MAPK and NF-?B. Silencing LRRC33 also promoted multiple TLR-mediated activation in human moDCs. Notably, LRRC33 expression could be down-regulated by TLR ligands LPS, poly I:C, or PGN through H3K4me3 and H3K27me3 modification. In LPS-conditioned moDCs, reduced enrichment of H3K4me3 and increased H3K27me3 could be observed at the promoter region of LRRC33. Furthermore, silencing H3K4me3-associated factors MLL and RBBP5 not only decreased the enrichment of H3K4me3 but also down-regulated expression of LRRC33, whereas the expression of LRRC33 was up-regulated after silencing H3K27me3-associated factors EZH2 and EED. Thus, our results suggest that LRRC33 and TLRs may form a negative-feedback loop, which is important for the maintenance of immune homeostasis.