Role of aryl hydrocarbon receptor (AhR) in rheumatoid arthritis

• Grant number: 11/02505-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): June 01, 2011
• Effective date (End): February 28, 2015
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Fernando de Queiroz Cunha
• Grantee: Jhimmy Talbot
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease that affect 1% of the worldwide population and it is characterized by infiltration of immune cells to the joints. The pathogenesis of RA involves enhancement of Th17-dependent immune response (pro-inflammatories). Recent studies revealed that activation of the aryl hydrocarbon receptor (AhR), an intracellular sensor of pollutants such as those present in cigarette smoke, plays an important role in the differentiation of Th17. It also has been showed that activation of AhR is related to expression of IL-17 and IL-22 in Th17 cells and increases the expression of pro-inflammatory cytokines such as IL-8 in synoviocytes. In a recent study we identified that RA patients have an increased expression of AhR mRNA. We also found that genetic polymorphisms in the AhR may be risk factors for the development of RA, being associated with a higher index of disease activity, especially in the presence of smoking. However, it was not yet determined the effect of genetic polymorphisms in the AhR activity, nor the role of activation of this receptor in the development of rheumatoid arthritis. The aim of this study is to evaluate the role of AhR in the development of rheumatoid arthritis. We propose: a) evaluate the influence of SNPs in the AhR in the expression and activity of this receptor, as well as the production of inflammatory mediators in cells isolated from patients with RA, b) determine the role of AhR activation in the pathogenesis of experimental arthritis investigating the mechanisms involved in the effect of AhR activation in murine models of antigen-induced arthritis and collagen-induced arthritis; c) In addition we intend to characterize, isolate and quantify a possible endogenous ligands of the AhR in the model of experimental arthritis and in patients with RA. (AU)