title: Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses.
abstract: C-type lectin receptors (CLRs) are an emerging family of pattern recognition receptors that recognizes pathogens or damaged tissue to trigger innate immune responses. However, endogenous ligands for CLRs are not fully understood. In this study, we sought to identify an endogenous ligand(s) for human macrophage-inducible C-type lectin (hMincle). A particular fraction of lipid extracts from liver selectively activated reporter cells expressing hMincle. MS analysis determined the chemical structure of the active component as cholesterol. Purified cholesterol in plate-coated and crystalized forms activates reporter cells expressing hMincle but not murine Mincle (mMincle). Cholesterol crystals are known to activate immune cells and induce inflammatory responses through lysosomal damage. However, direct innate immune receptors for cholesterol crystals have not been identified. Murine macrophages transfected with hMincle responded to cholesterol crystals by producing pro-inflammatory cytokines. Human dendritic cells expressed a set of inflammatory genes in response to cholesterol crystals, and this was inhibited by anti-human Mincle. Importantly, other related CLRs did not bind cholesterol crystals, whereas other steroids were not recognized by hMincle. These results suggest that cholesterol crystals are an endogenous ligand for hMincle and that they activate innate immune responses.
authors: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical institute of Bioregulation, Kyushu University, Fukuoka 812-8582, the Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582.
authors: Ryoko
authors: R
authors: Kiyotake
authors: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical institute of Bioregulation, Kyushu University, Fukuoka 812-8582.
authors: Masatsugu
authors: M
authors: Oh-Hora
authors: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical institute of Bioregulation, Kyushu University, Fukuoka 812-8582.
authors: Eri
authors: E
authors: Ishikawa
authors: the Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, and.
authors: Tomofumi
authors: T
authors: Miyamoto
authors: the Department of Ophthalmology, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582.
authors: Tatsuro
authors: T
authors: Ishibashi
authors: From the Division of Molecular Immunology, Research Center for Infectious Diseases, Medical institute of Bioregulation, Kyushu University, Fukuoka 812-8582, the Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan yamasaki@bioreg.kyushu-u.ac.jp.
authors: Sho
authors: S
authors: Yamasaki
mesh_terms: D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D003460:Crystallization; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C482593:CLEC4D protein, human; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D002784:Cholesterol
keywords: C-type lectin receptor; cholesterol crystals; cholesterol-binding protein; dendritic cell; inflammation; innate immunity; pattern recognition receptor (PRR)