The skin is a barrier tissue with a large surface area in contact with the external environment and its own microbial flora. As such, immune responses in the skin must be tightly regulated to avoid unwanted and potentially harmful responses to innocuous environmental substances and commensal antigens, while allowing responses to a wide array of cutaneous pathogens. The consequences of dysregulated immune responses in the skin can be dire and include inflammatory diseases such as psoriasis, scleroderma and pemphigus vulgaris, as well as allergic responses that lead to acute and chronic atopic dermatitis (AD) and allergic contact dermatitis (ACD). We have shown that transgenic overexpression of the cytokine thymic stromal lymphopoietin (TSLP) specifically in the skin results in severe cutaneous inflammation resembling chronic AD. This inflammation is characterized by hyperactivation of CD4+ T cells and development of a strongly biased Th2 response, elevated serum levels of IgE, and severe dermal infiltration T cells, mast cells and eosinophils. Surprisingly, TSLP-overexpressing mice lacking T cells still develop the characteristic cutaneous inflammation, suggesting that myeloid cells are sufficient for the induction of TSLP-induced inflammation in the skin. The central hypotheses driving the experiments proposed in this study are that regulated expression of TSLP by keratinocytes activates resident myeloid cells in the skin, resulting in the induction of a cutaneous Th2 response and allergic inflammation in the skin. Strongly dysregulated TSLP expression in the skin causes myeloid cell hyperactivation, resulting in severe cutaneous immunopathology and development of strong Th2- mediated inflammation. To test these hypotheses and further define the role of TSLP in driving allergic inflammation, we will 1) Define the molecular pathways that lead to TSLP expression in the skin, 2) Determine the role of resident skin myeloid cells in initiating TSLP-mediated skin inflammation, and 3) Define the mechanisms by which TSLP controls dendritic cell migration during induction of TH2 responses in vivo.

Public Health Relevance

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common inflammatory disease of the skin that are characterized by intense pruritus and chronic eczematous plaques that are often associated with a personal or family history of atopy. The etiology and pathogenesis of these diseases remain poorly characterized. The proposed experiments will help define the role of a novel cytokine, TSLP, in the induction and progression of AD and ACD. This in turn will help guide efforts to develop new interventions for these and other skin inflammatory diseases that directly or indirectly target TSLP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055695-05
Application #
8460069
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Cibotti, Ricardo
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$371,761
Indirect Cost
$168,613
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
Smigiel, Kate S; Richards, Elizabeth; Srivastava, Shivani et al. (2014) CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med 211:121-36
Srivastava, Shivani; Koch, Meghan A; Pepper, Marion et al. (2014) Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. J Exp Med 211:961-74
Srivastava, Shivani; Koch, Lisa K; Campbell, Daniel J (2014) IFN?R signaling in effector but not regulatory T cells is required for immune dysregulation during type I IFN-dependent inflammatory disease. J Immunol 193:2733-42
Smigiel, Kate S; Srivastava, Shivani; Stolley, J Michael et al. (2014) Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation. Immunol Rev 259:40-59
Duhen, Thomas; Campbell, Daniel J (2014) IL-1? promotes the differentiation of polyfunctional human CCR6+CXCR3+ Th1/17 cells that are specific for pathogenic and commensal microbes. J Immunol 193:120-9
Larson, Ryan P; Comeau, Michael R; Ziegler, Steven F (2013) Cutting edge: allergen-specific CD4 T cells respond indirectly to thymic stromal lymphopoietin to promote allergic responses in the skin. J Immunol 190:4474-7
Kitajima, Masayuki; Ziegler, Steven F (2013) Cutting edge: identification of the thymic stromal lymphopoietin-responsive dendritic cell subset critical for initiation of type 2 contact hypersensitivity. J Immunol 191:4903-7
Bell, Bryan D; Kitajima, Masayuki; Larson, Ryan P et al. (2013) The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat Immunol 14:364-71
Han, Hongwei; Headley, Mark B; Xu, Whitney et al. (2013) Thymic stromal lymphopoietin amplifies the differentiation of alternatively activated macrophages. J Immunol 190:904-12
Ziegler, Steven F; Roan, Florence; Bell, Bryan D et al. (2013) The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol 66:129-55

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