Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
CXCL16 as an Early Response Chemokine in Rat Adjuvant and K/BxN Serum Induced Arthritis Models.
Ruth2, Jeffrey H., Haas1, Chrisitian S., Amin2, M. Asif, III4, G. Kenneth Haines, Koch3, Alisa E.
We and others have previously shown that the transmembrane chemokine CXCL16 and its counterpart CXCR6 are important in the pathogenesis of rheumatoid arthritis (RA) predominantly via recruitment and stimulation of mononuclear cells. However, the expression pattern of CXCL16 during the development of RA and the optimal time point for therapeutic targeting remain unclear. In the present study we determined the spatiotemporal expression of CXCL16-CXCR6 in rat adjuvant induced arthritis (AIA), a rodent model for RA. We also examined joint swelling in CXCR6 deficient (CXCR6-/-) and wild-type (Wt) mice administered K/BxN serum, an acute model of RA.
Rat AIA synovial tissues (STs) were immunostained to determine the percentage of cells expressing CXCL16 and CXCR6. CXCL16 levels were also determined in serum and ankle homogenates using ELISA assays. CXCR6 expression was evaluated on rat macrophages and tested to induce rat macrophage migration towards soluble CXCL16 using a modified Boyden chemotaxis system. Lastly, CXCR6-/- and Wt C57BL/6 mice were primed to develop K/BxN serum induced arthritis and evaluated for joint swelling.
CXCL16 showed constitutive expression on endothelial cells in rat AIA, and was upregulated on both lining cells (LCs) and macrophages on day 14, prior to arthritis onset (p<0.05). CXCR6 was virtually absent in normal ST but was expressed on LCs and macrophages on day 14. CXCL16 levels in serum and joints were increased on day 4 of rat AIA, suggesting that CXCR6 positive inflammatory cells migrate very early to the ST in rat AIA. Rat macrophages constitutively expressed CXCR6 in vitro and migrated in response to the ligand in a dose-dependent manner. Finally, using the K/BxN serum induced arthritis model, CXCR6-/- mice showed significantly reduced joint swelling compared to Wt mice at day 5 after serum induction.
CXCL16 and CXCR6 are upregulated in the early course of rat AIA. CXCL16 positive macrophages and LCs are found predominantly prior arthritis onset. Rat macrophages express CXCR6 and migrate in response to CXCL16 in vitro. In addition, CXCR6-/- mice show significantly less joint swelling using in an acute model of RA, suggesting that CXCL16 and CXCR6 function early in disease development to recruit inflammatory cells to the joint. Our findings may help guide in vivo targeting strategies for the CXCL16-CXCR6 pathway in RA.
To cite this abstract, please use the following information:
Ruth, Jeffrey H., Haas, Chrisitian S., Amin, M. Asif, III, G. Kenneth Haines, Koch, Alisa E.; CXCL16 as an Early Response Chemokine in Rat Adjuvant and K/BxN Serum Induced Arthritis Models. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1417