Objective: Interleukin‐17 (IL‐17) is a proinflammatory cytokine that is expressed in the synovium of rheumatoid arthritis (RA) patients. This T cell cytokine is implicated in the initiation phase of arthritis. However, the role of IL‐17 during the effector phase of arthritis has still not been identified; this was the objective of the present study.Methods: Mice with collagen‐induced arthritis (CIA) were treated with polyclonal rabbit anti‐murine IL‐17 (anti–IL‐17) antibody–positive serum or normal rabbit serum after the first signs of arthritis. In addition, during a later stage of CIA mice were selected and treated with anti–IL‐17 antibody or control serum. Arthritis was monitored visually, and joint pathology was examined radiologically and histologically. Systemic IL‐6 levels were measured by enzyme‐linked immunosorbent assay, and local synovial IL‐1 and receptor activator of NF‐κB ligand (RANKL) expression was analyzed using specific immunohistochemistry.Results: Treatment with a neutralizing anti–IL‐17 antibody after the onset of CIA significantly reduced the severity of CIA. Radiographic analysis revealed marked suppression of joint damage in the knee and ankle joints. Histologic analysis confirmed the suppression of joint inflammation and showed prevention of cartilage and bone destruction after anti–IL‐17 antibody therapy. Systemic IL‐6 levels were significantly reduced after anti–IL‐17 antibody treatment. Moreover, fewer IL‐1β–positive and RANKL‐positive cells were detected in the synovium after treatment with neutralizing IL‐17. Interestingly, initiation of anti–IL‐17 antibody therapy during a later stage of CIA, using mice with higher clinical arthritis scores, still significantly slowed the progression of the disease.Conclusion: IL‐17 plays a role in early stages of arthritis, but also later during disease progression. Systemic IL‐6 was reduced and fewer synovial IL‐1–positive and RANKL‐positive cells were detected after neutralizing endogenous IL‐17 treatment, suggesting both IL‐1–dependent and IL‐1–independent mechanisms of action. Our data strongly indicate that IL‐17 neutralization could provide an additional therapeutic strategy for RA, particularly in situations in which elevated IL‐17 may attenuate the response to anti–tumor necrosis factor/anti–IL‐1 therapy.

TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial or host-derived ligands found in arthritic joints. Here, we show that TLR2 and TLR4, but not TLR9, are involved in the pathogenesis of autoimmune arthritis and play distinct roles in the regulation of T cells and cytokines. We investigated the involvement of TLR2, TLR4, and TLR9 in the progression of arthritis using IL-1 receptor antagonist–knockout (IL1rn^–/–) mice, which spontaneously develop an autoimmune T cell–mediated arthritis. Spontaneous onset of arthritis was dependent on TLR activation by microbial flora, as germ-free mice did not develop arthritis. Clinical and histopathological evaluation of IL1rn^–/–Tlr2^–/– mice revealed more severe arthritis, characterized by reduced suppressive function of Tregs and substantially increased IFN-γ production by T cells. IL1rn^–/–Tlr4^–/– mice were, in contrast, protected against severe arthritis and had markedly lower numbers of Th17 cells and a reduced capacity to produce IL-17. A lack of Tlr9 did not affect the progression of arthritis. While any therapeutic intervention targeting TLR2 still seems complicated, the strict position of TLR4 upstream of a number of pathogenic cytokines including IL-17 provides an interesting potential therapeutic target for rheumatoid arthritis.

Objective: MicroRNAs (miRNA) are a new class of regulatory elements. Altered expression of miRNA has been demonstrated in the inflamed joints of patients with rheumatoid arthritis (RA). The aim of this study was to examine the role of miRNA in the pathogenesis of autoimmune arthritis, using 2 murine models.Methods: Collagen‐induced arthritis (CIA) and K/BxN serum‐transfer arthritis were induced in wild‐type (WT) and miR‐155–deficient (miR‐155^−/−) mice. The severity of arthritis was determined clinically and histologically. Anticollagen antibodies and cytokines were measured by enzyme‐linked immunosorbent assay. The cellular composition of the draining lymph nodes after induction of CIA was measured by flow cytometry.Results: The miR‐155^−/− mice did not develop CIA. Deficiency in miR‐155 prevented the generation of pathogenic autoreactive B and T cells, since anticollagen antibodies and the expression levels of antigen‐specific T cells were strongly reduced in miR‐155^−/− mice. Moreover, Th17 polarization of miR‐155^−/− mouse T cells was impaired, as shown by a significant decrease in the levels of interleukin‐17 (IL‐17) and IL‐22. In the K/BxN serum‐transfer arthritis model, which only depends on innate effector mechanisms, miR‐155^−/− mice showed significantly reduced local bone destruction, attributed to reduced generation of osteoclasts, although the severity of joint inflammation was similar to that in WT mice.Conclusion: These results demonstrate that miR‐155 is essentially involved in the adaptive and innate immune reactions leading to autoimmune arthritis, and therefore miR‐155 might provide a novel target for the treatment of patients with RA.

Interleukin-17 (IL-17) is a T cell cytokine spontaneously produced by cultures of rheumatoid arthritis (RA) synovial membranes. High levels have been detected in the synovial fluid of patients with RA. The trigger for IL-17 is not fully identified; however, IL-23 promotes the production of IL-17 and a strong correlation between IL-15 and IL-17 levels in synovial fluid has been observed. IL-17 is a potent inducer of various cytokines such as tumor necrosis factor (TNF)-α, IL-1, and receptor activator of NF-κB ligand (RANKL). Additive or even synergistic effects with IL-1 and TNF-α in inducing cytokine expression and joint damage have been shown in vitro and in vivo. This review describes the role of IL-17 in the pathogenesis of destructive arthritis with a major focus on studies in vivo in arthritis models. From these studies in vivo it can be concluded that IL-17 becomes significant when T cells are a major element of the arthritis process. Moreover, IL-17 has the capacity to induce joint destruction in an IL-1-independent manner and can bypass TNF-dependent arthritis. Anti-IL-17 cytokine therapy is of interest as an additional new anti-rheumatic strategy for RA, in particular in situations in which elevated IL-17 might attenuate the response to anti-TNF/anti-IL-1 therapy.

Objective: The concept that intraarticular crystals of uric acid by themselves trigger episodes of painful gouty arthritis is inconsistent with the clinical reality. Patients with large deposits of monosodium urate monohydrate (MSU) crystals (tophi) do not necessarily experience gouty attacks. In fact, it is the excessive consumption of food or alcohol that elicits the inflammation of the acute gout attack. The aim of this study was to identify the precise mechanism that initiates flares of gouty arthritis.Methods: Human peripheral blood mononuclear cells (PBMCs) and murine macrophages were stimulated in vitro with MSU, free fatty acids (FFAs), or both in combination. Thereafter, production of interleukin‐1β (IL‐1β) and activation of caspase 1 were determined. Gouty arthritis was induced in mice with deficiencies in the genes for caspase 1, ASC, NALP3, or IL‐1β, and the lack of inflammasome activity during joint swelling or other joint pathologic features was investigated in these mice.Results: MSU crystals had no biologic effects on PBMCs from healthy subjects, whereas the FFA C18:0 in the presence of MSU crystals induced the release of large amounts of IL‐1β following engagement of Toll‐like receptor 2 (TLR‐2). Interaction of FFAs, but not alcohol, with TLR‐2 synergized with MSU crystals to induce an inflammatory reaction. An important event of MSU/FFA‐induced acute joint inflammation is the activation of the inflammasome. MSU/FFA‐induced release of IL‐1β was dependent on activation of caspase 1 and ASC, but surprisingly, not NALP3.Conclusion: The synergistic effect between FFAs and MSU crystals leads to ASC/caspase 1–driven IL‐1β release. This mechanism could explain how constitutionally derived metabolic events initiate attacks of gout via the induction of IL‐1β–mediated joint inflammation.