Psoriasis is a common chronic debilitating disease of the skin, nails and joints with a major impact on the quality of life to levels comparable to those seen in cancer, diabetes and heart disease. Psoriasis is now recognized as a complex genetic disorder caused by the interaction of specific genetic components and the environment. Our knowledge of these factors has greatly accelerated over the last several years with the identification of genetic loci involved in immune and epidermal function. This includes risk variants within the gene encoding for the IL23 receptor (IL-23R) that have been shown to influence not only the risk of psoriasis but also other chronic inflammatory diseases such as ankylosing spondylitis and Crohn's disease. The ligand for the IL-23 receptor, which is composed of the IL-23R and the IL-12R21 chains, is Il-23, which has been shown to have a major pathogenic role in number of inflammatory and autoimmune diseases through its effect on interleukin-17 (Th17) and interleukin-22 (Th22) producing T-cells. The biological effects of the risk variants in the IL-23R are unknown but they lead to amino-acid changes in the cytoplasmic domain of the receptor and are therefore likely to change downstream signaling. The hypothesis of this proposal is that the risk variants within the IL-23 receptor increase the activity of the receptor with resulting changes in the activity of Th17 and Th22 cells. To address this hypothesis, ex vivo and in vitro studies will be performed to address the following Specific Aims: 1) To determine whether the IL23R risk variants influence mRNA, protein and surface expression of the IL-23R in vitro and in vivo. 2) Determine whether the IL23R risk haplotype exerts an influence on IL-23R signaling in T-cells c) To determine whether the IL23R risk haplotype leads to differences in Th17 and Th22 differentiation, expansion and/or function. Successful completion of these studies should increase our understanding of the physiological and pathological role of the common variants within the interleukin-23 receptor and provide new insights into the mechanisms of diseases where these variants play a pathogenic role.

Public Health Relevance

It was recently demonstrated that coding variants in the gene for the interleukin(IL)-23 receptor increase risk of several chronic inflammatory diseases including psoriasis and Crohn's disease. IL-23 is a mediator that plays a central role in inflammatory processes but the role of these variants in its receptor and how they influence the biology of IL-23 is still unknown. The role of this project is to elucidate the physiologic role of these variants in the IL-23 receptor and provide new insights into the mechanisms of disease where these variants play a pathogenic role.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR060802-02
Application #
8244472
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Cibotti, Ricardo
Project Start
2011-03-17
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$126,900
Indirect Cost
$9,400
Name
University of Michigan Ann Arbor
Department
Dermatology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Xing, Xianying; Liang, Yun; Sarkar, Mrinal K et al. (2016) IL-17 Responses Are the Dominant Inflammatory Signal Linking Inverse, Erythrodermic, and Chronic Plaque Psoriasis. J Invest Dermatol 136:2498-2501
Wang, Yunmei; Golden, Jackelyn B; Fritz, Yi et al. (2016) Interleukin 6 regulates psoriasiform inflammation-associated thrombosis. JCI Insight 1:e89384
Swindell, William R; Sarkar, Mrinal K; Liang, Yun et al. (2016) Cross-Disease Transcriptomics: Unique IL-17A Signaling in Psoriasis Lesions and an Autoimmune PBMC Signature. J Invest Dermatol 136:1820-30
Rittié, Laure; Tejasvi, Trilokraj; Harms, Paul W et al. (2016) Sebaceous Gland Atrophy in Psoriasis: An Explanation for Psoriatic Alopecia? J Invest Dermatol 136:1792-800
Hawkes, Jason E; Gudjonsson, Johann E; Ward, Nicole L (2016) The Snowballing Literature on Imiquimod-Induced Skin Inflammation in Mice: A Critical Appraisal. J Invest Dermatol :
Johnston, A; Yin, Z; Gudjonsson, J E (2016) Still waters run deep: latent cytokine activity in nonlesional psoriasis skin. Br J Dermatol 174:19-20
Swindell, William R; Xing, Xianying; Fritz, Yi et al. (2016) Deficiency of myeloid-related proteins 8 and 14 (Mrp8/Mrp14) does not block inflammaging but prevents steatosis. Oncotarget 7:35535-35551
Thorleifsdottir, Ragna H; Sigurdardottir, Sigrun L; Sigurgeirsson, Bardur et al. (2016) HLA-Cw6 homozygosity in plaque psoriasis is associated with streptococcal throat infections and pronounced improvement after tonsillectomy: A prospective case series. J Am Acad Dermatol 75:889-896
Ward, Nicole L; Bhagathavula, Narasimharao; Johnston, Andrew et al. (2015) Erlotinib-induced skin inflammation is IL-1 mediated in KC-Tie2 mice and human skin organ culture. J Invest Dermatol 135:910-3

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