Th17-associated cells and signaling pathways are clearly important in the development of multiple autoimmune processes, including rheumatoid arthritis, multiple sclerosis, and psoriasis. IL23 is a prototypical driver of Th17-mediated inflammation, and we and others have shown that repeated injections of recombinant IL23 in mouse skin result in a psoriasiform dermatitis that mimics many of the features of human psoriasis in as little as 5 days. Among the ~20 known chemokine receptors, CC chemokine receptor-6 (CCR6) is particularly important for Th17-directed immune activity since it is both a marker for T cells that express the Th17 phenotype and a critical participant in several mouse models of autoimmune disease, including autoimmune encephalitis, collagen-induced arthritis, and psoriasis. We have previously shown that CCR6-deficient mice fail to develop psoriasiform dermatitis in skin following IL23 injection. Current models suggest that IL23 produced by dendritic cells (DCs) act to sustain dermal CC chemokine receptor-6 (CCR6)-expressing Th17 cells which then produce IL22 as a major downstream effector that stimulates epidermal hyperplasia through STAT3- mediated mechanisms in human skin. Positive feedback is provided by epidermal and dermal production of CCL20, the CCR6 ligand, potentially recruiting more CCR6+ T cells or CCR6+ antigen-presenting cells into inflamed psoriatic skin. While data from human studies are just beginning to implicate ??T cells in psoriasis and other autoimmune disease, our published data demonstrate that a novel population of CCR6+, V?3- T cell receptor (TCR) ?? low (GDL) T cells, distinct from resident dendritic epidermal ?? T cells (DETC), accumulates in murine epidermis following exposure to IL23 and is a major producer of IL22 and IL17 in murine epidermis. We hypothesize that 1) CCR6+ GDL T cells in skin may be critical innate immune cells for the delivery of IL22 and other cytokines that regulate epidermal hyperplasia and inflammation in skin in conditions such as psoriasis and 2) that antagonists of CCR6 or CCL20 would be effective therapeutic agents in several Th17- mediated autoimmune processes, including psoriasis, because of their effects on the trafficking and/or function of CCR6-expressing cells. Based on this hypothesis, we seek to better define the roles of CCR6 and ?? T cells in an IL23- and imiquimod-induced models of psoriasisform dermatitis in mice and to use novel computational methods to identify small molecule lead compounds that antagonize the function of either CCR6 or its ligand, CCL20. Our results will be validated with a SCID-hu psoriasis skin xenotransplant model.

Public Health Relevance

Psoriasis is an inflammatory skin disorder with systemic manifestations that affects 2-3% of the world's population. Chemokine receptors, particularly the Th17-associated chemokine receptor, CCR6, have been shown to play a central role in regulating a variety of autoimmune diseases, including psoriasis. The experiments proposed herein seek to better define the role of CCR6 and its ligand, CCL20, in murine models of psoriasiform dermatitis and to identify lead candidates (i.e., small molecules) that will block the CCR6/CCL20 chemotactic signaling pathway through in silico structural methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR063091-01A1
Application #
8502109
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2013-09-01
Project End
2018-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$314,313
Indirect Cost
$101,813
Name
Medical College of Wisconsin
Department
Dermatology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226