Session Information
Session 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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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-unique-role-for-il-18-receptor-%ce%b1-in-monocyte-migration-in-ra-and-kbxn-serum-transfer-arthritis/