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

J Leukoc Biol. 2014 Jul;96(1):17-26. doi: 10.1189/jlb.0813457. Epub 2014 Feb 18.

Abstract

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-κB. 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.

Keywords: H3K27me3; H3K4me3; dendritic cell; macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • DNA-Binding Proteins
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Enhancer of Zeste Homolog 2 Protein
  • Gene Silencing / drug effects
  • Gene Silencing / immunology*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / immunology
  • Histones / genetics
  • Histones / immunology
  • Homeostasis / drug effects
  • Homeostasis / genetics
  • Homeostasis / immunology*
  • Humans
  • Interferon Inducers / pharmacology
  • Latent TGF-beta Binding Proteins
  • Lipopolysaccharides / toxicity
  • Macrophages / cytology
  • Macrophages / immunology*
  • Methylation / drug effects
  • Mice
  • Mice, Knockout
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / immunology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology
  • Poly I-C / pharmacology
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / immunology
  • Receptor Activity-Modifying Proteins
  • Toll-Like Receptors / agonists
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology*
  • U937 Cells

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • EED protein, human
  • Eed protein, mouse
  • Histones
  • Interferon Inducers
  • KMT2A protein, human
  • Latent TGF-beta Binding Proteins
  • Lipopolysaccharides
  • NRROS protein, human
  • Nuclear Proteins
  • RBBP5 protein, human
  • RBBP5 protein, mouse
  • Receptor Activity-Modifying Proteins
  • Toll-Like Receptors
  • Myeloid-Lymphoid Leukemia Protein
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • Polycomb Repressive Complex 2
  • Poly I-C