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

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 FcRγ-associated activating receptor that senses damaged cells. To search an exogenous ligand(s), we screened pathogenic fungi using cell line expressing Mincle, FcRγ, 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 α-mannose but not mannan. Thus, Mincle may recognize specific geometry of α-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.

[1]  D. Underhill,et al.  Dectin-2 Is a Pattern Recognition Receptor for Fungi That Couples with the Fc Receptor γ Chain to Induce Innate Immune Responses* , 2006, Journal of Biological Chemistry.

[2]  S. Akira,et al.  Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans , 2007, Nature Immunology.

[3]  H. Ashbee Recent developments in the immunology and biology of Malassezia species. , 2006, FEMS immunology and medical microbiology.

[4]  A. Spurkland,et al.  Identification of lectin-like receptors expressed by antigen presenting cells and neutrophils and their mapping to a novel gene complex , 2004, Immunogenetics.

[5]  K. Takahashi,et al.  Identification and cloning of two novel allergens from the lipophilic yeast, Malassezia furfur. , 1998, Biochemical and biophysical research communications.

[6]  Alessandra Cambi,et al.  The C‐type lectin DC‐SIGN (CD209) is an antigen‐uptake receptor for Candida albicans on dendritic cells , 2003, European journal of immunology.

[7]  Christine A. Wells,et al.  The Macrophage-Inducible C-Type Lectin, Mincle, Is an Essential Component of the Innate Immune Response to Candida albicans1 , 2008, The Journal of Immunology.

[8]  S. Akira,et al.  A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages. , 1999, Journal of immunology.

[9]  Gordon D. Brown,et al.  C-type lectin receptors in antifungal immunity. , 2008, Trends in microbiology.

[10]  Osamu Takeuchi,et al.  The Roles of Two IκB Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection , 2004, The Journal of experimental medicine.

[11]  G. Donnarumma,et al.  Toll-like receptor 2 (TLR2) mediates intracellular signalling in human keratinocytes in response to Malassezia furfur , 2005, Archives of Dermatological Research.

[12]  S. Akira,et al.  Unresponsiveness of MyD88-deficient mice to endotoxin. , 1999, Immunity.

[13]  M. Tokunaga,et al.  Mechanistic basis of pre–T cell receptor–mediated autonomous signaling critical for thymocyte development , 2006, Nature Immunology.

[14]  R. K. Devlin,et al.  INVASIVE FUNGAL INFECTIONS CAUSED BY CANDIDA AND MALASSEZIA SPECIES IN THE NEONATAL INTENSIVE CARE UNIT , 2006, Advances in neonatal care : official journal of the National Association of Neonatal Nurses.

[15]  S. Gordon,et al.  The Beta-Glucan Receptor Dectin-1 Recognizes Specific Morphologies of Aspergillus fumigatus , 2005, PLoS pathogens.

[16]  H. Mittag Fine structural investigation of Malassezia furfur. II. The envelope of the yeast cells , 1995, Mycoses.

[17]  J. Hirabayashi,et al.  Glycoconjugate microarray based on an evanescent-field fluorescence-assisted detection principle for investigation of glycan-binding proteins. , 2008, Glycobiology.

[18]  Takashi Saito,et al.  NFAM1, an immunoreceptor tyrosine-based activation motif-bearing molecule that regulates B cell development and signaling. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Scheynius,et al.  Selective cloning of allergens from the skin colonizing yeast Malassezia furfur by phage surface display technology. , 1999, The Journal of investigative dermatology.

[20]  K. Drickamer Engineering galactose-binding activity into a C-type mannose-binding protein , 1992, Nature.

[21]  S. Yamasaki,et al.  Mincle is an ITAM-coupled activating receptor that senses damaged cells , 2008, Nature Immunology.

[22]  S. Gordon,et al.  Dectin-1 is required for beta-glucan recognition and control of fungal infection. , 2007, Nature immunology.

[23]  Gordon D. Brown Dectin-1: a signalling non-TLR pattern-recognition receptor , 2006, Nature Reviews Immunology.

[24]  Alessandra Cambi,et al.  Dendritic Cell Interaction with Candida albicans Critically Depends on N-Linked Mannan* , 2008, Journal of Biological Chemistry.

[25]  A. Scheynius,et al.  Atopic Eczema/Dermatitis Syndrome and Malassezia , 2002, International Archives of Allergy and Immunology.