title: Receptor Mincle promotes skin allergies and is capable of recognizing cholesterol sulfate.
abstract: Sterile (noninfected) inflammation underlies the pathogenesis of many widespread diseases, such as allergies and autoimmune diseases. The evolutionarily conserved innate immune system is considered to play a key role in tissue injury recognition and the subsequent development of sterile inflammation; however, the underlying molecular mechanisms are not yet completely understood. Here, we show that cholesterol sulfate, a molecule present in relatively high concentrations in the epithelial layer of barrier tissues, is selectively recognized by Mincle (Clec4e), a C-type lectin receptor of the innate immune system that is strongly up-regulated in response to skin damage. Mincle activation by cholesterol sulfate causes the secretion of a range of proinflammatory mediators, and s.c. injection of cholesterol sulfate results in a Mincle-mediated induction of a severe local inflammatory response. In addition, our study reveals a role of Mincle as a driving component in the pathogenesis of allergic skin inflammation. In a well-established model of allergic contact dermatitis, the absence of Mincle leads to a significant suppression of the magnitude of the skin inflammatory response as assessed by changes in ear thickness, myeloid cell infiltration, and cytokine and chemokine secretion. Taken together, our results provide a deeper understanding of the fundamental mechanisms underlying sterile inflammation.
authors.affiliation: Laboratory of Immunobiotechnology, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia; kostarnoy@yandex.ru.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Kostarnoy
authors.affiliation: Laboratory of Immunobiotechnology, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Petya G
authors.initials: PG
authors.lastname: Gancheva
authors.affiliation: Immunology Unit, Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, 30559 Hannover, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lepenies
authors.affiliation: Laboratory of Cellular Microbiology, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Amir I
authors.initials: AI
authors.lastname: Tukhvatulin
authors.affiliation: Laboratory of Cellular Microbiology, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Alina S
authors.initials: AS
authors.lastname: Dzharullaeva
authors.affiliation: Laboratory of Detection and Ultrastructural Analysis of Microorganisms, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.|Laboratory of Instrumental Methods and Organic Reagents, Vernadsky Institute of Geochemistry and Analytical Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia.
authors.forename: Nikita B
authors.initials: NB
authors.lastname: Polyakov
authors.affiliation: Laboratory of Detection and Ultrastructural Analysis of Microorganisms, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Daniil A
authors.initials: DA
authors.lastname: Grumov
authors.affiliation: Laboratory of Immunobiotechnology, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Daria A
authors.initials: DA
authors.lastname: Egorova
authors.affiliation: Laboratory of Evolutionary Developmental Biology, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119071 Moscow, Russia.
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Kulibin
authors.affiliation: Department of Pathology, M. F. Vladimirsky Moscow Regional Clinical Research Institute, 129110 Moscow, Russia.
authors.forename: Maxim A
authors.initials: MA
authors.lastname: Bobrov
authors.affiliation: Laboratory of Evolutionary Developmental Biology, Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119071 Moscow, Russia.|Laboratory of Cell Engineering, Ivanovsky Institute of Virology, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Malolina
authors.affiliation: Department of Cytology and Histology, St. Petersburg State University, 199034 St. Petersburg, Russia.
authors.forename: Pavel A
authors.identifier: 0000-0003-1624-6163
authors.initials: PA
authors.lastname: Zykin
authors.affiliation: Laboratory of Detection and Ultrastructural Analysis of Microorganisms, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Andrey I
authors.initials: AI
authors.lastname: Soloviev
authors.affiliation: Department of Control and Applied Mathematics, Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Russia.|Faculty of Computer Science, Big Data and Information Retrieval School, National Research University Higher School of Economics, Moscow 101000, Russia.
authors.forename: Evgeniy
authors.identifier: 0000-0003-0656-7625
authors.initials: E
authors.lastname: Riabenko
authors.affiliation: Scientific Research Centre Bioclinicum, 115088 Moscow, Russia.
authors.forename: Diana V
authors.initials: DV
authors.lastname: Maltseva
authors.affiliation: Scientific Research Centre Bioclinicum, 115088 Moscow, Russia.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Sakharov
authors.affiliation: Department of Translational Oncology, P. Hertsen Moscow Oncology Research Institute, National Center of Medical Radiological Research, Moscow 125284, Russia.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Tonevitsky
authors.affiliation: Laboratory of Molecular Biotechnology, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Lyudmila V
authors.initials: LV
authors.lastname: Verkhovskaya
authors.affiliation: Laboratory of Cellular Microbiology, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Denis Y
authors.initials: DY
authors.lastname: Logunov
authors.affiliation: Laboratory of Immunobiotechnology, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Boris S
authors.initials: BS
authors.lastname: Naroditsky
authors.affiliation: Laboratory of Gene Engineering of Pathogenic Microorganisms, N. F. Gamaleya Federal Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gintsburg
mesh_terms: D000818:Animals; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D002788:Cholesterol Esters / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000473:pathology
chemical_list: D018925:Chemokines; D002788:Cholesterol Esters; C113583:Clecsf8 protein, mouse; D016207:Cytokines; D037181:Lectins, C-Type; D008565:Membrane Proteins; C007045:cholesteryl sulfate
keywords: Mincle; allergy; cholesterol sulfate; innate immunity; sterile inflammation