title: Epigenetically modulated LRRC33 acts as a negative physiological regulator for multiple Toll-like receptors.
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.
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and.
authors.forename: Shiyue
authors.initials: S
authors.lastname: Mei
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and.
authors.forename: Xue
authors.initials: X
authors.lastname: Liang
authors.affiliation: Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking, China.
authors.forename: Shihua
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and.
authors.forename: Yue
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and.
authors.forename: Yongzhe
authors.initials: Y
authors.lastname: Che
authors.affiliation: Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Peking, China.
authors.forename: Robert
authors.initials: R
authors.lastname: Chunhua Zhao
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and ryang@nankai.edu.cn zhang_zhujun@nankai.edu.cn.
authors.forename: Zhujun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Nankai University School of Medicine, and Key Laboratory of Bioactive Materials, Ministry of Education, The College of Life Sciences, Nankai University, Nankai, China; and ryang@nankai.edu.cn zhang_zhujun@nankai.edu.cn.
authors.forename: Rongcun
authors.initials: R
authors.lastname: Yang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D020868:Gene Silencing / Q000187:drug effects / Q000276:immunology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D053779:Latent TGF-beta Binding Proteins; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000276:immunology; D058261:Receptor Activity-Modifying Proteins; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D020298:U937 Cells
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C491488:EED protein, human; C107275:Eed protein, mouse; D006657:Histones; D007369:Interferon Inducers; C497422:KMT2A protein, human; D053779:Latent TGF-beta Binding Proteins; D008070:Lipopolysaccharides; C582014:NRROS protein, human; D009687:Nuclear Proteins; C470552:RBBP5 protein, human; C557020:RBBP5 protein, mouse; D058261:Receptor Activity-Modifying Proteins; D051193:Toll-Like Receptors; D051788:Myeloid-Lymphoid Leukemia Protein; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D063151:Polycomb Repressive Complex 2; D011070:Poly I-C
keywords: H3K27me3; H3K4me3; dendritic cell; macrophage