Hypersensitivity to environmental stimuli is a fundamental feature of atopy that manifests itself through atopic dermatitis or eczema. Mast cells are distributed widely in the skin and increased in number in atopic dermatitis (AD). Antigen cross-linking of the high affinity receptor for IgE (FcepsilonRI) on mast cells causes their degranulation, release of histamine and other preformed mediators, as well as several proinflammatory cytokines and chemokines. The sphingolipid metabolite sphingosine-1-phosphate (S1P) is a new addition to the bioactive compounds produced and released by activated mast cells. FcepsilonRI triggering activates sphingosine kinase (SphK) leading to formation and secretion of S1P which in turn transactivates its receptors S1P(1) and S1P(2). S1P(1) is critical for migration of mast cells toward antigen and S1P(2) is required for degranulation. This information emerged from studies of rodent mast cells and nothing is yet known of the functions of S1P in human mast cells and particularly in skin allergic responses and dermatoses. We propose that, similar to rodent mast cells, S1P produced by activation of SphKs and consequently S1PRs by FcepsilonRI triggering plays a crucial role in human skin mast cell functions including degranulation, cytokine and chemokine release, and their movement to sites of inflammation. The objectives of this application are: to examine role of SphKs, S1P, and S1P receptors in degranulation and secretion of chemokines and cytokines; to elucidate the involvement of S1PRs in movement of human mast cells towards antigen; to evaluate the involvement of S1P in survival and development of human mast cells; and finally, to determine how S1P is transported out of human mast cells to signal in an autocrine/paracrine fashion. AD, one of the most common dermatoses, is a chronic inflammatory skin disease affecting about 2- 3% of the adult population, skin mast cells are very responsive to G protein activators and their ability to secrete and respond to S1P suggests that that this potent lipid mediator could act in positive feedback loop to aggravate and prolong the allergic cutaneous response and the development of atopic dermatitis, contact allergy and psoriasis. The results of the proposed studies will enhance our understanding of mast cell activation, recruitment and proliferation, and could provide the basis for development of new therapeutic agents targeting S1P functions to treat inflammatory disorders of skin, such as atopic dermatitis and eczema. ? ? ? ?
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