Sensing Lipids with Mincle: Structure and Function

Abstract

Mincle is a C-type lectin receptor that has emerged as an important player in innate immunity through its capacity to recognize a wide range of lipidic species derived from damaged/altered self and foreign microorganisms. Self-ligands include sterols (e.g., cholesterol), and β-glucosylceramides, and the protein SAP130, which is released upon cell death. Foreign lipids comprise those from both microbial pathogens and commensals and include glycerol, glucose and trehalose mycolates, and glycosyl diglycerides. A large effort has focused on structural variation of these ligands to illuminate the structure–activity relationships required for the agonism of signaling though Mincle and has helped identify key differences in ligand recognition between human and rodent Mincle. These studies in turn have helped identify new Mincle ligands, further broadening our understanding of the diversity of organisms and lipidic species recognized by Mincle. Finally, progress toward the development of Mincle agonists as vaccine adjuvants providing humoral and cell-mediated immunity with reduced toxicity is discussed.

Asymmetric Total Synthesis of Mycobacterial Diacyl Trehaloses Demonstrates a Role for Lipid Structure in Immunogenicity

“… 32 − 34 The activation of Mincle results in downstream expression of cytokines, chemokines, and growth factors and leads to recruitment of inflammatory cells to the site of activation as a central part of the innate immune response to Mtb . 33 Several other Mtb cell wall glycolipids have been identified as Mincle activators, 34 , 35 and there is growing interest in using these Mincle ligands for the development of novel vaccine adjuvants. 36 …”

Mitigating Coronavirus Induced Dysfunctional Immunity for At-Risk Populations in COVID-19: Trained Immunity, BCG and “New Old Friends”

“…In a similar manner, Mincle suppresses Th17 immune responses, which as well have been suggested in coronavirus immunopathology and vaccine-induced immune enhancement ( 213 , 214 ). It was only recently discovered that activation of the Mincle receptor is a key activation pathway for Complete Freund’s Adjuvant (CFA), the “gold standard” adjuvant for eliciting cell-mediated immunity (CMI) in research models ( 215 – 217 ).…”

C-type lectin receptor-mediated immune recognition and response of the microbiota in the gut

“…Dectin-2 is a type II transmembrane protein with a short cytoplasmic tail and its extracellular domain is responsible for ligand binding. Like that of Dectin-2, Mincle-dependent signaling also occurs via FcRγ culminating in a pathway involving Syk and the CARD9–Bcl-10–MALT1 complex to activate NF-κB, which then leads to several pro-inflammatory responses and adaptive immune responses against pathogens [43, 44].…”

“…These clues indicate that we may pay more attention to the possible relationship between Mincle and the pathogenesis of IBD [60]. Furthermore, Mincle can recognize various lipid components released from both host cells and microorganisms released upon cell death [44, 61]. In relation to Dectin-3, we found that the development of dextran sulfate sodium (DSS)-induced colitis can be promoted by Dectin-3 deficiency in mouse models challenged with Candida tropicalis [46], supporting its role in fungal recognition in the gut.…”