Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses.

Article Details

Citation

Kiyotake R, Oh-Hora M, Ishikawa E, Miyamoto T, Ishibashi T, Yamasaki S

Human Mincle Binds to Cholesterol Crystals and Triggers Innate Immune Responses.

J Biol Chem. 2015 Oct 16;290(42):25322-32. doi: 10.1074/jbc.M115.645234. Epub 2015 Aug 20.

PubMed ID
26296894 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
CholesterolC-type lectin domain family 4 member EProteinHumans
Unknown
Ligand
Details
Pharmaco-transcriptomics
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
CholesterolApproved InvestigationalAQP9366
upregulated
Cholesterol results in increased expression of AQP9 mRNA15q21.3
CholesterolApproved InvestigationalAREG374
upregulated
Cholesterol results in increased expression of AREG mRNA4q13.3
CholesterolApproved InvestigationalCCL16346
upregulated
Cholesterol results in increased expression of CCL1 mRNA17q12
CholesterolApproved InvestigationalCCL46351
upregulated
Cholesterol results in increased expression of CCL4 mRNA17q12
CholesterolApproved InvestigationalCLEC5A23601
upregulated
Cholesterol results in increased expression of CLEC5A mRNA7q34
CholesterolApproved InvestigationalCSF11435
upregulated
Cholesterol results in increased expression of CSF1 mRNA1p13.3
CholesterolApproved InvestigationalDCSTAMP81501
upregulated
Cholesterol results in increased expression of DCSTAMP mRNA8q22.3
CholesterolApproved InvestigationalFLT12321
upregulated
Cholesterol results in increased expression of FLT1 mRNA13q12.3
CholesterolApproved InvestigationalGP1BA2811
upregulated
Cholesterol results in increased expression of GP1BA mRNA17p13.2
CholesterolApproved InvestigationalHBEGF1839
upregulated
Cholesterol results in increased expression of HBEGF mRNA5q31.3
CholesterolApproved InvestigationalIL1B3553
upregulated
Cholesterol results in increased expression of IL1B mRNA2q14.1
CholesterolApproved InvestigationalIL1RN3557
upregulated
Cholesterol results in increased expression of IL1RN mRNA2q14.1
CholesterolApproved InvestigationalINHBA3624
upregulated
Cholesterol results in increased expression of INHBA mRNA7p14.1
CholesterolApproved InvestigationalKITLG4254
upregulated
Cholesterol results in increased expression of KITLG mRNA12q21.32
CholesterolApproved InvestigationalLPL4023
upregulated
Cholesterol results in increased expression of LPL mRNA8p21.3
CholesterolApproved InvestigationalOCSTAMP128506
upregulated
Cholesterol results in increased expression of OCSTAMP mRNA20q13.12
CholesterolApproved InvestigationalPSAT129968
upregulated
Cholesterol results in increased expression of PSAT1 mRNA9q21.2
CholesterolApproved InvestigationalRGCC28984
upregulated
Cholesterol results in increased expression of RGCC mRNA13q14.11
CholesterolApproved InvestigationalSLC1A36507
upregulated
Cholesterol results in increased expression of SLC1A3 mRNA5p13.2
CholesterolApproved InvestigationalSLC28A364078
upregulated
Cholesterol results in increased expression of SLC28A3 mRNA9q21.32-q21.33
CholesterolApproved InvestigationalSLC7A58140
upregulated
Cholesterol results in increased expression of SLC7A5 mRNA16q24.2
CholesterolApproved InvestigationalTIMP37078
upregulated
Cholesterol results in increased expression of TIMP3 mRNA22q12.3
CholesterolApproved InvestigationalTM4SF19116211
upregulated
Cholesterol results in increased expression of TM4SF19 mRNA3q29