Project 4 - TLR2-mediatecl control of inflammatory arthritis

点击翻译按钮获取中文摘要

Rheumatoid arthritis (RA) is a debilitating chronic inflammatory disease affecting approximately 1% of the population worldwide. Present understanding of molecular and cellular events involved in RA is limited, though innate immune responses are considered critical to development of chronic joint inflammation and bone loss seen in RA patients. Collagen-induced arthritis (CIA) is one of the most commonly used animal models of RA; better understanding of the immunopathogenesis of CIA has the potential to provide important information on the mechanisms of human RA. The innate immune response is the first-line of defense in which Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns (PAMPs) and exert subsequent immune responses against a variety of pathogens. Indeed, signaling through TLRs on innate immune cells induces the production of critical cytokines responsible for T helper (Th) cell polarization and subsequent adaptive immune responses. Mycobacterial adjuvants used for CIA induction are known to be rich in ligands for these TLRs, particularly TLR2. The overall goal of this project is to better understand the mechanism by which TLR2 contributes to the development of arthritis. During early RA, antigenpresenting cells such as dendritic cells, macrophages, and B cells respond to PAMP-mediated signaling and produce inflammatory cytokines. Clinically, inhibition of these cytokines dramatically improves symptoms and can be effective in preventing RA disease progression. Recently, Th17 cells, which produce the signature cytokine IL-17, have been implicated in the etiopathogenesis of RA. Our preliminary findings show that IL-6 and IL-17 mediate many of the chronic inflammatory changes in CIA including bone loss, and that TLR2- deficient mice (TLR2-K0) are relatively resistant to this process. We hypothesize that TLR2 signaling plays a pivotal role in the immune response activation that triggers CIA pathogenesis leading to joint inflammation and bone loss. We will test this hypothesis via the following Specific Aims: 1) Assess the role of TLR2- dependent induction of IL-17-producing cells in the pathogenesis of CIA using flow cytometry, ImageStream technology, qRT-PCR, and ELISA; 2) Characterize the role of TLR2 expression in synoviocyte responses during the development of CIA; 3) Identify TLR2-dependent phosphoproteins in both bone marrow-derived dendritic cells and synoviocytes (using phosphoproteomics) as a means of identifying host-derived "activators" of CIA. Near term, our study results will broaden understanding of CIA. Long term, studies of this nature will help identify pathways to support development of novel therapies to treat RA.