A2B adenosine receptor modulation of TNF-alpha expression in mouse rheumatoid arthritis
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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that leads to destruction of articular cartilage and subchondral bone at the synovial joints. Clinically, RA is characterized by swelling, tenderness and destruction of synovial joints, which results in severe disability and premature mortality. In the RA disease state, inflammation in the synovial compartment is regulated by a complex cytokine and chemokine network, including tumor necrosis factor α (TNFα), which has been clinically demonstrated a key mediator of RA pathogenesis. TNFα can be found in elevated levels in the synovial fluid and serum of RA patients and the role of the cytokine in both the inflammation and bone destruction of RA suggests it is important in the understanding of disease progression as well as the development of therapeutic targets. Many of the biological processes that mediate RA, including bone turnover and cartilage resorption, involve signaling pathways that are mediated by adenosine and its receptors. The A2B adenosine receptor (A2BAR) is highly expressed in the synoviocytes of RA patients and the receptor has a similar expression profile in humans and mice. The goal of this thesis was to use a mouse model of RA to understand how the A2B adenosine receptor modulates TNFα and other destructive enzymes that contribute to the progression of the disease. A collagen antibody-induced arthritis (CAIA) mouse model was used to determine the effect of A2BAR ablation on systemic and joint-specific TNFα expression. Comparable arthritic conditions were observed in CAIA mice of both A2BAR knockout (KO) and wild-type (WT) genotypes and the absence of the A2BAR gene did not result in any observable differences in the gross arthritic state created in each genotype. Immunohistochemistry analysis of TNFα expression in mouse paws revealed that paw joints from CAIA A2BAR KO mice exhibited more robust TNFα staining compared to CAIA WT specimens of the same treatment duration. ELISA analysis of the serum showed that only CAIA A2BAR KO mice had greater serum production of TNFα at day 10 after induction of arthritis. TNFα and matrix metalloproteinase-9 mRNA expression were also elevated in KO CAIA knee joints in comparison to WT CAIA knee joints; however, WT CAIA mice were found to have higher levels of aggrecanase mRNA compared to KO mice. These results suggest that while the loss of A2BAR activity leads to a hyper-inflammatory state, the A2B adenosine receptor alone is not responsible for the progressive inflammation of the synovial joints associated with rheumatoid arthritis.