Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses

• Published in: The Journal of biological chemistry 2015-10, Vol.290 (42), p.25322-25332
• Main Authors: Kiyotake, Ryoko, Oh-hora, Masatsugu, Ishikawa, Eri, Miyamoto, Tomofumi, Ishibashi, Tatsuro, Yamasaki, Sho
• Format: Article
• Language: English
• Subjects: Animals; C-type lectin receptor; Cell Line; Cholesterol - chemistry; Cholesterol - metabolism; cholesterol crystals; cholesterol-binding protein; Crystallization; dendritic cell; Humans; Immunity, Innate; Immunology; inflammation; Inflammation Mediators - metabolism; innate immunity; Lectins, C-Type - metabolism; Mice; pattern recognition receptor (PRR); Protein Binding; Receptors, Immunologic - metabolism; Transcription, Genetic
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.645234

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. Background: Cholesterol crystals are involved in various chronic inflammatory diseases; however, direct pattern recognition receptors (PRRs) recognizing cholesterol crystals have not been identified. Results: We purified endogenous components interacting with human Mincle and identified cholesterol. Conclusion: Direct interaction of human Mincle with cholesterol crystals activates innate immune responses. Significance: Human Mincle could be a therapeutic target of chronic inflammation.