title: TLR2/MyD88-dependent and -independent activation of mast cell IgE responses by the skin commensal yeast Malassezia sympodialis.
abstract: Atopic eczema (AE) is a chronic inflammatory skin disease. Approximately 50% of adult AE patients have allergen-specific IgE reactivity to the skin commensal yeast Malassezia spp. Due to the ruptured skin barrier in AE, it is likely that Malassezia can come into contact with mast cells, which are known to be involved in AE. We therefore hypothesized that Malassezia spp. can activate mast cells. Bone marrow-derived mast cells (BMMCs) were generated from wild type, TLR2, TLR4, and MyD88 gene-deleted mice and cocultured with Malassezia sympodialis extract. We recorded that M. sympodialis induced release of cysteinyl leukotrienes in a dose-dependent manner in nonsensitized and IgE-anti-trinitrophenyl-sensitized BMMCs, respectively, with three times higher levels in the latter type of cells. IgE-sensitized BMMCs also responded by degranulation as assessed by release of beta-hexosaminidase, increased MCP-1 production through a MyD88-independent pathway, and activated phosphorylation of the MAPK ERK1/2. Furthermore, M. sympodialis enhanced the degranulation of IgE receptor cross-linked wild-type BMMCs and altered the IL-6 release dose-dependently. This degranulation was independent of TLR2, TLR4, and MyD88, whereas the IL-6 production was dependent on the TLR2/MyD88 pathway and MAPK signaling. In conclusion, M. sympodialis extract can activate nonsensitized and IgE-sensitized mast cells to release inflammatory mediators, to enhance the IgE-mediated degranulation of mast cells, and to modulate MAPK activation and by signaling through the TLR2/MyD88 pathway to modify the IL-6 production of IgE receptor cross-linked mast cells. Collectively, these findings indicate that M. sympodialis can activate mast cells and might thus exacerbate the inflammatory response in AE.
authors.affiliation: Department of Medicine Solna, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden. Christine.Selander@ki.se
authors.forename: Christine
authors.initials: C
authors.lastname: Selander
authors.forename: Camilla
authors.initials: C
authors.lastname: Engblom
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nilsson
authors.forename: Annika
authors.initials: A
authors.lastname: Scheynius
authors.forename: Carolina Lunderius
authors.initials: CL
authors.lastname: Andersson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015550:Cell Degranulation / Q000276:immunology*; D003876:Dermatitis, Atopic / Q000276:immunology / Q000382:microbiology; D003881:Dermatomycoses / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology; D008290:Malassezia / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D007073:Immunoglobulin E; D020928:Mitogen-Activated Protein Kinases