C-type lectin Mincle is an activating receptor for pathogenic fungus,Malassezia

Abstract

Mincle (also called as Clec4e and Clecsf9) is a C-type lectin receptor expressed in activated phagocytes. Recently, we have demonstrated that Mincle is an FcR␥-associated activating receptor that senses damaged cells. To search an exogenous ligand(s), we screened pathogenic fungi using cell line expressing Mincle, FcR␥, and NFAT-GFP reporter. We found that Mincle specifically recognizes the Malassezia species among 50 different fungal species tested. Malassezia is a pathogenic fungus that causes skin diseases, such as tinea versicolor and atopic dermatitis, and fatal sepsis. However, the specific receptor on host cells has not been identified. Mutation of the putative mannose-binding motif within C-type lectin domain of Mincle abrogated Malassezia recognition. Analyses of glycoconjugate microarray revealed that Mincle selectively binds to ␣-mannose but not mannan. Thus, Mincle may recognize specific geometry of ␣-mannosyl residues on Malassezia species and use this to distinguish them from other fungi. Malassezia activated macrophages to produce inflammatory cytokines/ chemokines. To elucidate the physiological function of Mincle, Mincle-deficient mice were established. Malassezia-induced cytokine/chemokine production by macrophages from Mincle ؊/؊ mice was significantly impaired. In vivo inflammatory responses against Malassezia was also impaired in Mincle ؊/؊ mice. These results indicate that Mincle is the first specific receptor for Malassezia species to be reported and plays a crucial role in immune responses to this fungus.ITAM ͉ macrophages ͉ signal transduction

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…Our data also suggest that ATF3 constitutes a negative feedback mechanism that attenuates obesity-induced macrophage activation in adipose tissue. On the other hand, we found that macrophage-inducible C-type lectin (Mincle, Clec4e, or Clecsf 9), a pathogen sensor for pathogenic fungi and Mycobacterium tuberculosis [49,50], is induced in adipose tissue macrophages in obesity, at least partly, through the saturated fatty acid-TLR4 pathway [51]. Yamasaki et al reported that Mincle senses cell death as well to induce proinflammatory cytokine production [52].…”

Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis

“…The Mincle KO mice and enhanced green fluorescence protein (Egfp) Tg mice on the C57BL/6J genetic background were kindly provided by Drs Shizuo Akira and Masaru Okabe (Osaka University) 16,37 , respectively. We crossed these mice to generate the Mincle KO-Egfp Tg mice for the BMT experiments.…”

“…Macrophage-inducible C-type lectin (Mincle, Clec4e or Clecsf9) is a pathogen sensor that recognizes pathogenic fungi and Mycobacterium tuberculosis [13][14][15][16] , and as the name implies, it is induced in macrophages by lipopolysaccharide through Toll-like receptor 4 (TLR4; ref. 17).…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…23 Galectin-3 on the surface of murine macrophages can bind to the b-1,2 mannosides of C. albicans. 107,108 In human neutrophil, Galectin-3 plays an important role in phagocytosing C. albicans hyphae, but not C. albicans yeasts. 109 Dectin-2 is another PRR for phagocytic cells to recognize C. albicans mannans.…”

“…49,51,142,143 Similarly, fungal recognition by Mincle induces the production of cytokines, including MIP-2, KC, IL-10 and TNF-a. 107,114 PRRs of dendritic cells (DCs)…”