Corynomycolic acid-containing glycolipids signal through the pattern recognition receptor Mincle

Peet, Phillip L. van der; Gunawan, Christian; Torigoe, Shota; Yamasaki, Satoshi; Williams, Spencer J.

doi:10.1039/c5cc00085h

Cited by 59 publications

(76 citation statements)

References 51 publications

(41 reference statements)

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“…1 and SI Appendix, Figs. S1-S3), as reported recently (24). Thus, the total number of carbon atoms in the fatty acid did not appear to be the key parameter driving Mincle activity.…”

Section: Deciphering the Structural Features Required For (Glyco)lipidsupporting

confidence: 56%

Rational design of adjuvants targeting the C-type lectin Mincle

Decout

Silva‐Gomes

Drocourt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

134

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The advances in subunit vaccines development have intensified the search for potent adjuvants, particularly adjuvants inducing cellmediated immune responses. Identification of the C-type lectin Mincle as one of the receptors underlying the remarkable immunogenicity of the mycobacterial cell wall, via recognition of trehalose-6,6′-dimycolate (TDM), has opened avenues for the rational design of such molecules. Using a combination of chemical synthesis, biological evaluation, molecular dynamics simulations, and protein mutagenesis, we gained insight into the molecular bases of glycolipid recognition by Mincle. Unexpectedly, the fine structure of the fatty acids was found to play a key role in the binding of a glycolipid to the carbohydrate recognition domain of the lectin. Glucose and mannose esterified at O-6 by a synthetic α-ramified 32-carbon fatty acid showed agonist activity similar to that of TDM, despite their much simpler structure. Moreover, they were seen to stimulate proinflammatory cytokine production in primary human and murine cells in a Mincle-dependent fashion. Finally, they were found to induce strong Th1 and Th17 immune responses in vivo in immunization experiments in mice and conferred protection in a murine model of Mycobacterium tuberculosis infection. Here we describe the rational development of new molecules with powerful adjuvant properties. mycobacteria | glycolipid | innate immunity

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“…1 and SI Appendix, Figs. S1-S3), as reported recently (24). Thus, the total number of carbon atoms in the fatty acid did not appear to be the key parameter driving Mincle activity.…”

Section: Deciphering the Structural Features Required For (Glyco)lipidsupporting

confidence: 56%

Rational design of adjuvants targeting the C-type lectin Mincle

Decout

Silva‐Gomes

Drocourt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

134

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“…A common Mincle ligand signature structure has been predicted based on a number of identified ligands (6,7,(33)(34)(35) in combination with the Mincle protein structure (9)(10)(11)(12). A polar head consisting of glucose or mannose and a hydrophobic chain appear to be the minimum requirement for ligand activity.…”

Section: Discussionmentioning

confidence: 99%

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Nagata

Izumi

Ishikawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

141

126

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Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 × Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

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“…As reported in detail previously, the lack of cell wall mycolates in DSM43989 may be due to a deficiency in DIP0789, a putative enoyl coenzyme A (enoyl-CoA) hydratase (Ott et al, submitted). In a recent publication, van der Peet et al reported the chemical synthesis of corynomycolic acids and tested trehalose and glucose mono-and diesters thereof for interactions with human and mouse Mincle using reporter cell lines (34). Notably, not only TDCM but also TMCM, and even glucose monocorynomycolate, triggered Mincle signaling and reporter gene activation.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, not only TDCM but also TMCM, and even glucose monocorynomycolate, triggered Mincle signaling and reporter gene activation. In contrast, when TDB was reduced toward a monosaccharide, namely, glucose behenate, it lost stimulatory activity (34). Similarly, testing of trehalose mono-and diesters of fatty acids of various lengths identified exclusively the diester forms as strong Mincle activators (36).…”

Section: Discussionmentioning

confidence: 99%

“…A stimulatory effect of purified trehalose dicorynomycolate (TDCM) from C. glutamicum on macrophages was shown previously, without characterization of the receptors involved (33). Recently, synthetic corynomycolates were demonstrated to be recognized through mouse and human Mincle by using a reporter cell system (34). However, the role for Mincle and other CLRs in the recognition of corynebacteria by innate immune cells has not been tested.…”

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confidence: 99%

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Toll-Like Receptor 2 and Mincle Cooperatively Sense Corynebacterial Cell Wall Glycolipids

et al. 2017

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Nontoxigenic Corynebacterium diphtheriae and Corynebacterium ulcerans cause invasive disease in humans and animals. Host sensing of corynebacteria is largely uncharacterized, albeit the recognition of lipoglycans by Toll-like receptor 2 (TLR2) appears to be important for macrophage activation by corynebacteria. The members of the order Corynebacterineae (e.g., mycobacteria, nocardia, and rhodococci) share a glycolipid-rich cell wall dominated by mycolic acids (termed corynomycolic acids in corynebacteria). The mycolic acid-containing cord factor of mycobacteria, trehalose dimycolate, activates the C-type lectin receptor (CLR) Mincle. Here, we show that glycolipid extracts from the cell walls of several pathogenic and nonpathogenic Corynebacterium strains directly bound to recombinant Mincle in vitro. Macrophages deficient in Mincle or its adapter protein Fc receptor gamma chain (FcR␥) produced severely reduced amounts of granulocyte colony-stimulating factor (G-CSF) and of nitric oxide (NO) upon challenge with corynebacterial glycolipids. Consistently, cell wall extracts of a particular C. diphtheriae strain (DSM43989) lacking mycolic acid esters neither bound Mincle nor activated macrophages. Furthermore, TLR2 but not TLR4 was critical for sensing of cell wall extracts and whole corynebacteria. The upregulation of Mincle expression upon encountering corynebacteria required TLR2. Thus, macrophage activation by the corynebacterial cell wall relies on TLR2-driven robust Mincle expression and the cooperative action of both receptors.KEYWORDS C-type lectin receptor, Mincle, Toll-like receptor, macrophage, Corynebacterium diphtheriae, cell wall lipids, mycolate, mycolic acid, corynomycolate D iphtheria caused by toxin-producing Corynebacterium diphtheriae is a severe, life-threatening infection, which has become rare in Europe due to the efficacy and coverage of toxoid immunization but still causes a considerable burden of disease globally. Corynebacterium ulcerans and Corynebacterium pseudotuberculosis can also harbor the tox gene encoding diphtheria toxin (1) and in addition may secrete the exotoxin phospholipase D, a virulence factor involved in caseous lymphadenitis of sheep and goats (2, 3). Rates of infections with nontoxigenic strains of C. diphtheriae, including bloodstream infections and endocarditis, appear to be increasing in Europe (4,5). Of the 90 species that comprise the genus Corynebacterium, many inhabit the human skin or mucosa as commensals (6), with C. striatum, C. tuberculostearicum, C. amycolatum, and C. jeikeium being typical examples of skin inhabitants, whereas C. urealyticum and C. glucuronolyticum are frequently found in the urogenital tract. All

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Corynomycolic acid-containing glycolipids signal through the pattern recognition receptor Mincle

Cited by 59 publications

References 51 publications

Rational design of adjuvants targeting the C-type lectin Mincle

Rational design of adjuvants targeting the C-type lectin Mincle

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Toll-Like Receptor 2 and Mincle Cooperatively Sense Corynebacterial Cell Wall Glycolipids

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