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TLR2/MyD88-Dependent and -Independent Activation of Mast Cell IgE Responses by the Skin Commensal Yeast Malassezia sympodialis¹

Christine Selander^2,*, Camilla Engblom, Gunnar Nilsson, Annika Scheynius^* and Carolina Lunderius Andersson

^* Department of Medicine Solna, Clinical Allergy Research Unit and Clinical Immunology and Allergy Unit, Karolinska Institutet and University Hospital Solna, Stockholm, Sweden

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 β-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Swedish Research Council; by the Center for Allergy Research, Karolinska Institutet; through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and the Karolinska Institutet; by the Consul Th C Bergh Foundation; by the Ellen, Walter and Lennart Hesselman Foundation; by the Åke Wiberg Foundation; and by the Magnus Bergvall Foundation.

² Address correspondence and reprint requests to Christine Selander, Clinical Allergy Research Unit L2:04, Karolinska Institutet and University Hospital Solna, S-171 76 Stockholm, Sweden. E-mail address: Christine.Selander{at}ki.se

³ Abbreviations used in this paper: AE, atopic eczema; BMMC, bone marrow-derived mast cell; Wt, wild type; TNP, trinitrophenyl.