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Abstract Number: 937

A Unique Role for IL-18 Receptor-α in Monocyte Migration in RA and K/BxN Serum Transfer Arthritis

W. Alexander Stinson1, Phillip L. Campbell1, Jeffrey Ruth2, Gautam Edhayan2, Ray A. Ohara2, Nicholas Lepore3, Alisa E. Koch4, David A. Fox2 and M. Asif Amin2, 1Division of Rheumatology, University of Michigan Medical Center, Ann Arbor, MI, 2Internal Medicine, Division of Rheumatology, University of Michigan Medical Center, Ann Arbor, MI, 3University of Michigan, Division of Rheumatology, University of Michigan Medical Center, Ann Arbor, MI, 4Department of Veteran's Affairs and University of Michigan, Ann Arbor, MI

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: IL-1, inflammatory arthritis, monocytes, rheumatoid arthritis (RA) and synovial fluid

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Session Information

Title: Rheumatoid Arthritis - Animal Models I

Session Type: Abstract Submissions (ACR)

Background/Purpose:  Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by monocyte (MN) recruitment. Proinflammatory cytokines and their corresponding receptors play an important role in the progression of RA by increasing MN infiltration. Soluble IL-18 receptor-α (IL-18Rα) is highly expressed in RA synovial fluids (SFs), synovial tissues (STs), ST fibroblasts, and CD4+ T cells. In this study, we determined the contribution of IL-18Rα in the pathogenesis of RA.

Methods:  Western blotting was performed to examine IL-18Rα expression on tumor necrosis factor-α (TNF-α) stimulated MNs. We performed MN chemotaxis in modified Boyden chambers to determine the role of IL-18Rα in MN migration in vitro. To examine MN homing in the context of RA, we employed an RA ST-severe combined immunodeficient (SCID) mouse chimera using RA SFs with or without IL-18Rα neutralizing antibody. We harvested RA ST after 48 hours and examined tissue sections by immunofluorescence. K/BxN serum transfer arthritis was performed in IL-18Rα null and wild type (wt) mice to determine the role of the IL-18Rα in arthritis and MN recruitment. Cytokine levels were determined by enzyme linked immunosorbent assays (ELISAs) in ankle homogenates of IL-18Rα null and wt mice. 

Results: TNF-α stimulated normal human MNs showed a marked increase of IL-18Rα expression. After finding increased expression in IL-18Rα, we determined its role in MN migration. IL-18Rα partially mediates TNF-α and RA SF-induced MN migration, as anti-human IL-18Rα antibody significantly inhibited TNF-α and RA SF mediated MN migration in vitro (p<0.05). We further investigated the importance of IL-18Rα to MN migration in human RA by using the RA-SCID mouse chimera. RA SF injected into the chimeric human ST resulted in MN recruitment to the ST, which was decreased in the presence of mouse anti-human IL-18Rα, suggesting that IL-18Rα is essential in RA SF-stimulated MN migration in vivo. We determined the contribution of IL-18Rα in inflammatory arthritis by performing K/BxN serum transfer arthritis. IL-18Rα null mice were resistant to K/BxN arthritis, showing a significant decrease in ankle circumference compared to wt mice (p<0.05). Mouse ankles harvested on day 9 of maximal arthritis showed a significant decrease in MN migration in IL-18Rα null mouse joint sections compared to wt mice, as determined by staining for F4/80, a MN/macrophage marker. To determine the mechanism of decreased MN ingress and defective arthritis in IL-18Rα null mice, ELISAs were performed for proinflammatory cytokines using mouse ankle homogenates. We found a >3 fold decrease in IL-1β levels in IL-18Rα null mouse ankles compared to wt mouse ankles (p<0.05), suggesting that the IL-18Rα is critical in inflammatory cytokine expression. 

Conclusion: These studies suggest that IL-18Rα is inducible in MNs and plays an important role in MN migration in vitro and in vivo. IL-18Rα null mice have impaired MN recruitment and arthritis development in part due to decreased IL-1β. These results provide strong evidence that the IL-18Rα plays an important role in MN ingress in RA and in a rodent model of inflammatory arthritis and may be a novel therapeutic target for RA.


Disclosure:

W. A. Stinson,
None;

P. L. Campbell,
None;

J. Ruth,
None;

G. Edhayan,
None;

R. A. Ohara,
None;

N. Lepore,
None;

A. E. Koch,

Eli Lily,

3;

D. A. Fox,
None;

M. A. Amin,
None.

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