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.innate immunity | sterile inflammation | allergy | Mincle | cholesterol sulfate

Innate immunity in allergy

“…Dectin‐2 has been implicated in allergic inflammation to house dust mites with Th2 polarization . A recent study shows that Mincle recognizes not only glycolipids but also self‐derived cholesterol sulfate in skin epithelial cells and is involved in the induction of allergic skin inflammatory response …”

C-Type Lectin-Like Receptors: Head or Tail in Cell Death Immunity

“…MINCLE is expressed by antigen-presenting cells including macrophages, neutrophils, DCs and B cells (76). Its expression is induced by several inflammatory stimuli and stresses, such as lipopolysaccharide (LPS), tumor necrosis factor (TNF), IL-6 and saturated fatty acids (76)(77)(78)(79) and was found over-expressed in numerous inflammatory diseases (77,(80)(81)(82)(83)(84)(85)(86). Interestingly, a polymorphism in this receptor has been linked to protection against rheumatoid arthritis in humans (87).…”

“…Alternatively, as neutrophils also express MINCLE, the use of antibodies may have exerted pleotropic effects by directly targeting or depleting neutrophils (98). Although MINCLE contributes to inflammation and immunity to contain the insult and initiate tissue repair, it can amplify collateral tissue damage and was therefore demonstrated to be implicated in numerous inflammatory diseases such as obesity, rheumatoid arthritis, allergic contact dermatitis, ischemic stroke, traumatic brain injury, hepatitis, sepsis, and multiple sclerosis (77,(80)(81)(82)(83)(84)(85)(86). Besides, MINCLE recognizes cholesterol crystals abundantly present in atherosclerotic plaques, triggering in macrophages the production of pro-inflammatory molecules (91).…”

“…Besides, MINCLE recognizes cholesterol crystals abundantly present in atherosclerotic plaques, triggering in macrophages the production of pro-inflammatory molecules (91). MINCLE was also shown to play a specific role on plasmacytoid DCs in skin allergies by recognizing cholesterol sulfate and inducing secretion of pro-inflammatory mediators such as IL-1α, IL-1β, MIP-1α, and MIP-1β (82). Furthermore, β-GlcCer whose accumulation leads to the systemic inflammation of Gaucher disease, was also characterized as a ligand for MINCLE, able to potentiate acquired immune response (90).…”

Expression and function of macrophage-inducible C-type lectin (Mincle) in inflammation driven parturition in fetal membranes and myometrium

“…Macrophage‐inducible C‐type lectin (Mincle; gene name CLEC4E) is a CLR that was first identified in 1999 as a downstream target of the transcription factor NF‐interleukin (IL)‐6 in macrophages . Mincle expression is strongly induced in response to several inflammatory stimuli and stresses, such as lipopolysaccharide (LPS), tumour necrosis factor (TNF), IL‐6 and saturated fatty acids and in various diseases characterized by increased inflammation, including obesity, rheumatoid arthritis, allergic contact dermatitis, ischaemic stroke, traumatic brain injury and hepatitis .…”