Interleukin‐17 receptor deficiency results in impaired synovial expression of interleukin‐1 and matrix metalloproteinases 3, 9, and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall–induced arthritis

Abstract

Objective. To examine the role of interleukin-17 receptor (IL-17R) signaling in cartilage destruction and its interrelationship with synovial IL-1 expression during chronic reactivated streptococcal cell wall (SCW)-induced arthritis. Methods. SCW arthritis was repeatedly induced in wild-type (WT) and IL-17R-deficient (IL-17R-/-) mice. At different time points, joint inflammation was assessed by using calipers to measure joint swelling. On day 42, mice were killed, and knee joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL-17R -/-mice after 5 repeated injections of SCW fragments. Results. IL-17R

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).…”

“…IL-17 is highly pathogenic to cartilage and bone in various T cell-mediated experimental models of arthritis, including SCW arthritis, and has been shown to be able to take over the catabolic functions of IL-1 (32,34). Importantly, recent evidence indicates that conditioned medium from TLR-4-activated dendritic cells is sufficient to induce Th17 differentiation when TGF␤ is added (47).…”

“…The T cell cytokine IL-17 has been implicated in cartilage destruction during chronic SCW arthritis (32), and TLR-4 activation has been shown to drive IL-17 production during experimental arthritis (14). Since in the present study, the expression of a number of cytokines closely related to the development and survival of Th17 cells was found to be reduced in TLR-4 -/-mice ( Figure 4B), we analyzed the T cell cytokine response to nonspecific, as well as antigen-specific, stimulation.…”

“…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.…”

Crucial role of the interleukin‐6/interleukin‐17 cytokine axis in the induction of arthritis by glucose‐6‐phosphate isomerase

“…Judging from these findings, GPI-induced arthritis is considered a useful murine model for analyzing the role of CD4ϩ T cells in the effector phase of the arthritis. Several studies have examined the roles of Th17 cells, a distinct lineage of CD4ϩ effector T cells, in various arthritis models (14)(15)(16)(17). CIA was shown to be partially suppressed in IL-17-deficient mice (16), whereas it was exacerbated in IFN␥-deficient mice or IFN␥ receptor-deficient mice (18)(19)(20).…”