T cell dependence of chronic destructive murine arthritis induced by repeated local activation of toll‐like receptor–driven pathways: Crucial role of both interleukin‐1β and interleukin‐17

Abstract

Objective. The pathogenesis of rheumatoid arthritis is often linked to bacterial infections. The present study was undertaken to develop a mouse model of chronic destructive arthritis induced by repeated intraarticular (IA) exposure to bacterial cell wall fragments and to investigate the cytokine dependence of this model.Methods. Mice that were deficient in various cytokines were injected IA with cell wall fragments of Streptococcus pyogenes on days 0, 7, 14, and 21. The development of chronic destructive arthritis was compared between groups of mice lacking different cytokines, to assess which cytokines were crucial for development of chronic destructive arthritis.Results. Repeated exposure of a joint to S pyogenes cell wall fragments resulted in the development of chronic destructive arthritis. In mice deficient in recombination-activating gene 2, streptococcal cell wall (SCW)-directed T cell reactivity was found and chronic arthritis did not develop, implicating T cells in the generation of chronic SCW-induced arthritis. Interleukin-17 (IL-17) receptor-deficient mice showed a reduction of joint destruction in the chronic stage, implicating a detrimental role of the recently discovered IL-17-producing T helper cells (Th17 cells). IL-23 ex-pression was apparent during the late stages of arthritis. Joint swelling was no longer dependent on tumor necrosis factor ␣ (TNF␣) after the last flare, and pronounced cartilage damage was found after 28 days in TNF␣-deficient mice. In contrast, IL-1␤-deficient mice were fully protected against joint swelling and cartilage and bone destruction during the late stages of disease.Conclusion. These findings indicate that the TNF␣ dependence of arthritis is lost during the erosive stage, when Th17 cells become crucial. IL-1␤ dependence remains strong, consistent with its pivotal role in the generation of Th17 cells.

Shift from toll‐like receptor 2 (TLR‐2) toward TLR‐4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR‐4–mediated interleukin‐17 production

“…In contrast, cartilage and bone erosion does not necessarily correspond to the severity of inflammation, since these processes are principally driven by other factors, such as IL-1, IL-17, and MMPs. The chronic phase of SCW arthritis has previously been shown to be dependent on the T cell cytokine IL-17, which is responsible for the expression of IL-1 and some MMPs, and for irreversible cartilage destruction, among other pathologic changes (31,32).…”

“…In this model, the TNFdependent macrophage-driven process during the acute phase turns into an IL-1/IL-17-dependent T cell-driven process during the chronic phase (31,32). Here, we demonstrate a shift from TLR-2 dependency in the acute phase of arthritis toward TLR-4 dependency in the chronic phase, manifested by reduced expression of mediators and markers of cartilage and bone destruction and a lower antigen-specific IL-17 response in TLR-4 -/-mice.…”

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

“…Subsequent intravenous injection of SCW fragments could result in a flare reaction, as seen in the rat model (49). More recently, modified versions of this model have been described in which mice either are injected once intraarticularly or receive multiple intraarticular injections, resulting in continued inflammation (50). The initial intraarticular injection of SCW fragments induces acute joint inflamma-tion, which resolves within a week.…”

“…The initial intraarticular injection of SCW fragments induces acute joint inflamma-tion, which resolves within a week. Repeated injections (Ն3) result in the development of chronic arthritis (50).…”

Induction, function and regulation of IL‐17‐producing T cells

“…An independent study demonstrated that IL-1a/b double knockout mice were also resistant to EAE, whereas IL-1ra À/À mice were more susceptible [46]. It was also demonstrated that IL-1b is a critical mediator of chronic destructive murine arthritis, probably through the induction of Th17 cells [47]. In a murine model of arthritis, where disease is induced by commensal bacteria in IL-1Ra À/À , a defect in TLR4 controlled the production of IL-17 by inducing IL-23 and IL-1 production by APC [48].…”