Receptor Mincle promotes skin allergies and is capable of recognizing cholesterol sulfate

A.V. Kostarnoy*, P.G. Gancheva, B. Lepenies, A.I. Tukhvatulin, A.S Dzharullaeva, N.B. Polyakov, D.A. Grumov, D.A. Egorova, A.Y. Kulibin, M.A. Bobrov, E.A. Malolina, P.A. Zykin, A.I. Soloviev, E. Riabenko, D.V. Maltseva, D.A. Sakharov, A. Tonevitsky, L.V. Verkhovskaya, D.Y. Logunov, B.S. Naroditsky, A.L. Gintsburg
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. Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):E2758-E2765. doi: 10.1073/pnas.1611665114. Epub 2017 Mar 14.