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Review
. 2018 Jan 17:8:1940.
doi: 10.3389/fimmu.2017.01940. eCollection 2017.

Identification and Biological Activity of Synthetic Macrophage Inducible C-Type Lectin Ligands

Chriselle D Braganza  1   2 , Thomas Teunissen  1   2 , Mattie S M Timmer  1   2 , Bridget L Stocker  1   2
Affiliations
Review

Identification and Biological Activity of Synthetic Macrophage Inducible C-Type Lectin Ligands

Chriselle D Braganza et al. Front Immunol. .

Abstract

The macrophage inducible C-type lectin (Mincle) is a pattern recognition receptor able to recognize both damage-associated and pathogen-associated molecular patterns, and in this respect, there has been much interest in determining the scope of ligands that bind Mincle and how structural modifications to these ligands influence ensuing immune responses. In this review, we will present Mincle ligands of known chemical structure, with a focus on ligands that have been synthetically prepared, such as trehalose glycolipids, glycerol-based ligands, and 6-acylated glucose and mannose derivatives. The ability of the different classes of ligands to influence the innate, and consequently, the adaptive, immune response will be described, and where appropriate, structure-activity relationships within each class of Mincle ligands will be presented.

Keywords: C-type lectin; Mincle; adjuvant; damage-associated molecular pattern; glycolipid; pathogen-associated molecular pattern.

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Figures

Figure 1
Figure 1
(A) The activation of macrophage inducible C-type lectin (Mincle) on antigen-presenting cells by ligands leads to the induction of the FcRγ-Syk-Card9 pathway and NF-κB-mediated gene expression. (B) Crystal structure of human Mincle (18), with the carbohydrate recognition domain EPN motif indicated in yellow, the lipophilic region in green, and the cholesterol recognition/interaction amino acid consensus-like motif in purple.
Figure 2
Figure 2
Isolated trehalose dimycolate (TDM) (1) from natural sources, such as Mycobacterium tuberculosis, consists of a mixture of up to 500 different structures with a variety of side-chain functional groups and different lipid lengths (n, x, y, and z). Structures 1a–f are representative homogenous TDMs synthesized by Baird et al. (27, 28).
Figure 3
Figure 3
Other branched trehalose diesters (TDEs). trehalose dicorynomycolate (TDCM) (2), first isolated from Corynebacterium species, occurs naturally as a mixture of chain lengths. Various TDCMs and dehydroxy derivatives have been synthesized, as have the maradolipids, which have been first isolated from the dauer larva stage of Caenorhabditis elegans. Of these branched TDEs, TDCM (1) and maradolipids (6a–f) have been confirmed to be macrophage inducible C-type lectin agonists (42, 43, 47, 48).
Figure 4
Figure 4
Non-branched trehalose diesters (TDEs), including linear TDEs (60), brartemicin derivatives (61, 62), fluorescent TDE probes (63), and a trehalose based affinity probe (64). Of these derivatives, only the linear TDEs (7d–i), the lipophilic brartemicin derivatives (9a–f), and the fluorescent TDE probes (10a–d) have been shown to be macrophage inducible C-type lectin agonists.
Figure 5
Figure 5
Structures of the trehalose monoesters (69, 71), trehalose monomycolates (27, 28), and trehalose monocorynomycolates (47), of which representative family members (e.g., 12h, 12i, 13d, and 14a) have been determined to be macrophage inducible C-type lectin agonists.
Figure 6
Figure 6
Glucose monoesters have been isolated from different species of Mycobacterium and Corynebacterium, including glucose monomycolates (15a–g) and glucose monocorynomycolates (15h–l). These, and related monosaccharide monoesters (15m–r) have been examined for their ability to activate macrophage inducible C-type lectin (Mincle), with specific glucose monoesters (e.g., 15a,b,i–l,n,p–t, 16a,h,r, and 17b) being selected and found to directly bind and activate Mincle (, , , –77).
Figure 7
Figure 7
Structures of synthetic glycerol monoesters that have been evaluated as macrophage inducible C-type lectin (Mincle) ligands (27, 47, 84, 85). Of these, 18a, 18b, 18c, 19k, and 20k have been determined to be agonists for human Mincle and not murine Mincle.
Figure 8
Figure 8
Several glycosyl diacylglycerides have been isolated from bacterial species such as the Mycobacterium tuberculosis, Streptococcus pneumoniae, and Lactobacillus plantarum, as well as rom Malassezia sp. and shown to be macrophage inducible C-type lectin (Mincle) ligands (–90). Mincle agonists include glyceroglycolipids (e.g., 21a–c, g–i), mannoside (22), and glucosyl diglycerides (24a–g, 25a,b, and 26). β-Glucosylceramides (27a,b), isolated from dead human and mouse cells, have also been determined to be Mincle agonists (91).
Figure 9
Figure 9
Structures of steroid ligands that bind macrophage inducible C-type lectin through an alternative binding site containing a cholesterol recognition/interaction amino acid consensus-like motif (20, 95).
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