title: Glycerol monomycolate is a novel ligand for the human, but not mouse macrophage inducible C-type lectin, Mincle.
abstract: An array of lipidic compounds that constitute the cell wall of mycobacteria is recognized by host receptors. Examples include trehalose dimycolate (TDM), which is a major surface-exposed glycolipid of mycobacteria, that interacts with the macrophage inducible C-type lectin, Mincle, and exerts its highly potent adjuvant functions. Recent evidence has suggested that glycerol monomycolate (GroMM), another mycolate-containing lipid species produced by mycobacteria, can stimulate innate immune cells; however, its specific host receptors have yet to be identified. We here demonstrated that cell transfectants expressing human Mincle (hMincle) reacted to both TDM and GroMM, while those expressing mouse Mincle (mMincle) only reacted to TDM and failed to recognize GroMM. Studies using domain swap chimeras confirmed that the ectodomain of hMincle, but not that of mMincle, interacted with GroMM, and site-directed mutagenesis analyses revealed that short stretches of amino acid residues at positions 174-176 and 195-196 were involved in GroMM recognition. To further substantiate the differential recognition of GroMM by hMincle and mMincle, hMincle transgenic/mMincle knock-out mice (i.e. hMincle(+) mice) were established and compared with non-transgenic mice (i.e. mMincle(+) mice). We showed that macrophages derived from hMincle(+) mice were activated by GroMM and produced inflammatory cytokines, whereas those derived from mMincle(+) mice did not exhibit any reactivity to GroMM. Furthermore, local inflammatory responses were elicited in the GroMM-injected skin of hMincle(+), but not mMincle(+) mice. These results demonstrated that GroMM is a unique ligand for hMincle that is not recognized by mMincle.
authors.affiliation: From the Laboratory of Cell Regulation, Institute for Virus Research and the Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: From the Laboratory of Cell Regulation, Institute for Virus Research and the Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Morita
authors.affiliation: the Department of Food and Nutrition, Faculty of Contemporary Human Life Science, Tezukayama University, Nara 631-8585, Japan.
authors.forename: Nagatoshi
authors.initials: N
authors.lastname: Fujiwara
authors.affiliation: the Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan, and.
authors.forename: Daiki
authors.initials: D
authors.lastname: Mori
authors.affiliation: the Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: the Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
authors.affiliation: the Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan, and yamasaki@bioreg.kyushu-u.ac.jp.
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: From the Laboratory of Cell Regulation, Institute for Virus Research and the Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan, msugita@virus.kyoto-u.ac.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugita
mesh_terms: D000818:Animals; D005260:Female; D006017:Glycolipids / Q000378:metabolism; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050178:Monoglycerides / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009161:Mycobacterium / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000378:metabolism*; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology
chemical_list: C482593:CLEC4D protein, human; C113583:Clecsf8 protein, mouse; D006017:Glycolipids; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; D050178:Monoglycerides; D011971:Receptors, Immunologic; C539336:glycerol monomycolate
keywords: Glycerol Monomycolate; Host-Pathogen Interactions; Innate Immunity; Lipids; Macrophages; Mincle; Mycobacteria; Transgenic Mice
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