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.

Public Health Relevance

Rheumatoid Arthritis (RA) is a debilitating autoimmune disease afflicting approximately 1% of the woridwide population. Despite recent advances in biologic therapy, many patients are not able to achieve remission, suggesting a need for further research in this area. Using the murine collagen-induced arthritis (CIA) model, we propose to investigate innate immune responses that are critical for the development of arthritis. Information collected from these studies could inform development of novel therapies to treat RA.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103625-02
Application #
8523931
Study Section
Special Emphasis Panel (ZRR1-RI-B)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$300,970
Indirect Cost
$96,922
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Kovak, Matthew R; Saraswati, Sarika; Schoen, David J et al. (2014) Investigation of galectin-3 function in the reproductive tract by identification of binding ligands in human seminal plasma. Am J Reprod Immunol 72:403-12
Pawar, Snehalata A; Shao, Lijian; Chang, Jianhui et al. (2014) C/EBP? deficiency sensitizes mice to ionizing radiation-induced hematopoietic and intestinal injury. PLoS One 9:e94967
Winchell, Caylin G; Graham, Joseph G; Kurten, Richard C et al. (2014) Coxiella burnetii type IV secretion-dependent recruitment of macrophage autophagosomes. Infect Immun 82:2229-38
Nakagawa, Mayumi; Coleman, Hannah N; Wang, Xuelian et al. (2014) IL-12 secretion by Langerhans cells stimulated with Candida skin test reagent is mediated by dectin-1 in some healthy individuals. Cytokine 65:202-9
Maddukuri, Leena; Ketkar, Amit; Eddy, Sarah et al. (2014) The Werner syndrome protein limits the error-prone 8-oxo-dG lesion bypass activity of human DNA polymerase kappa. Nucleic Acids Res 42:12027-40
Kennedy, Joshua L; Schroeder, Nikhila; Palacios, Thamiris et al. (2014) Fifty-five-year-old man with chronic yeast infections. Allergy Asthma Proc 35:415-22
Fortune, Danielle E; Lin, Yi-Pin; Deka, Ranjit K et al. (2014) Identification of lysine residues in the Borrelia burgdorferi DbpA adhesin required for murine infection. Infect Immun 82:3186-98
Coleman, Carrie B; McGraw, Jennifer E; Feldman, Emily R et al. (2014) A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo. PLoS Pathog 10:e1003916
Groshong, Ashley M; Fortune, Danielle E; Moore, Brendan P et al. (2014) BB0238, a presumed tetratricopeptide repeat-containing protein, is required during Borrelia burgdorferi mammalian infection. Infect Immun 82:4292-306
Beenken, Karen E; Mrak, Lara N; Zielinska, Agnieszka K et al. (2014) Impact of the functional status of saeRS on in vivo phenotypes of Staphylococcus aureus?sarA mutants. Mol Microbiol 92:1299-312

Showing the most recent 10 out of 16 publications