Pro-inflammatory cytokines and chemokines play critical roles in rheumatoid arthritis (RA). Recent studies have addressed the role of toll-like receptors (TLR)s in the development and progression of RA. An important role of various TLRs in the animal model of arthritis has been demonstrated. TLR4 and endogenous TLR4 ligands such as hyaluronan and heat shock protein (HSP)22 are highly expressed in synovial tissue from RA patients compared with healthy donors further implicating TLRs in RA pathogenesis. However the signaling pathways that regulate endogenous TLR4 ligands-induced TLR activation in RA are not fully understood. Recent studies demonstrated that adaptor proteins 2-arrestin 1 and 2 associating with TRAF6, I:B1, and NF:B1p105 negatively regulate TLR signaling. Our data demonstrated for the first time that 2-arrestin 2 knockout (KO) mice exhibited more severe arthritis in the collagen antibody-induced arthritis (CAIA) model compared to wild type (WT) mice. Furthermore, we observed that 2-arrestin 1 and 2 expression are increased in splenocytes and fibroblast-like synoviocytes (FLS) in the collagen-induced arthritis (CIA) mice compared to the control mice. It was also demonstrated that LPS- and the endogenous TLR4 ligand low molecular weight hyaluronan (LMW-HA)- induced TNF1, IL-6 and IL-10 production were augmented in splenocytes from 2- arrestin 2 KO mice compared to WT mice. These findings led us to propose the hypothesis that up-regulation of 2-arrestin 1 and 2 expression suppresses inflammation in collagen-induced arthritis by negative regulation of inflammatory cell responses.
The specific aim i s to investigate the role of 2-arrestin 1 and 2 as negative regulators of the inflammatory response in collagen-induced arthritis. 2-arrestin 1 and 2 expression in splenic macrophages, CD4+ and CD8+ T lymphocytes, B lymphocytes, dendritic cells (DC)s, polymorphonuclear leukocyte (PMN)s and FLS correlation to the disease severity in the mouse CIA model will be examined. Once the specific immune cells that exhibit altered expression of 2-arrestins are identified, the role of 2-arrestin 1 and 2 expression on activation of these cells will be examined using the lentiviral expression system to overexpress 2-arrestins or knock down 2-arrestins with RNAi. Understanding 2-arrestins-dependent signaling pathways that regulate pro- and anti-inflammatory gene expression will provide novel insights into the pathogenesis of RA from which innovative targeted interventions can evolve.

Public Health Relevance

This project investigates the role of 2-arrestin 1 and 2 as negative regulators of inflammatory response in collagen-induced arthritis. Understanding 2-arrestin 1 and 2 expression in correlation to the disease severity and its cellular specificity in the collagen-induced arthritis model in mice and role of 2-arrestin 1 and 2 expression on endogenous Toll-like receptor ligands and other stimuli induced inflammatory response will provide novel insights into the pathogenesis of rheumatoid arthritis from which innovative targeted interventions can evolve.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI079248-02
Application #
7911699
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Peyman, John A
Project Start
2009-08-11
Project End
2011-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$73,750
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Li, Pengfei; Neubig, Richard R; Zingarelli, Basilia et al. (2012) Toll-like receptor-induced inflammatory cytokines are suppressed by gain of function or overexpression of G?(i2) protein. Inflammation 35:1611-7
Fan, Hongkuan; Li, Pengfei; Zingarelli, Basilia et al. (2011) Heterotrimeric G?(i) proteins are regulated by lipopolysaccharide and are anti-inflammatory in endotoxemia and polymicrobial sepsis. Biochim Biophys Acta 1813:466-72
Li, Pengfei; Cook, James A; Gilkeson, Gary S et al. (2011) Increased expression of beta-arrestin 1 and 2 in murine models of rheumatoid arthritis: isoform specific regulation of inflammation. Mol Immunol 49:64-74
Fan, Hongkuan; Bitto, Alessandra; Zingarelli, Basilia et al. (2010) Beta-arrestin 2 negatively regulates sepsis-induced inflammation. Immunology 130:344-51