IL-17 Induces Monocyte Migration in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is in part mediated by the migration of monocytes from blood to RA synovial tissue, where they differentiate into macrophages and secrete inflammatory cytokines and chemokines. The T cell cytokine IL-17 is expressed in the RA synovial tissue and synovial fluid. To better understand the mechanism by which IL-17 might promote inflammation, its role in monocyte trafficking was examined. In vivo, IL-17 mediates monocyte migration into sponges implanted into SCID mice. In vitro, IL-17 was chemotactic, not chemokinetic, for monocytes at the concentrations detected in the RA synovial fluid. Further, IL-17-induced monocyte migration was mediated by ligation to IL-17RA and RC expressed on monocytes and was mediated through p38MAPK signaling. Finally, neutralization of IL-17 in RA synovial fluid or its receptors on monocytes significantly reduced monocyte migration mediated by RA synovial fluid. These observations suggest that IL-17 may be important in recruiting monocytes into the joints of patients with RA, supporting IL-17 as a therapeutic target in RA. IL-17 (also known as IL-17A) is the hallmark cytokine of a novel Th cell population termed TH17, which has altered the TH1/TH2 paradigm in immune biology (1, 2). IL-17 is produced by memory CD4+ T lymphocytes. TGF-β, IL-1β, IL-6, and IL-23 are important for the polarization of TH17 cells from naive human CD4+ T cells, and the absence of TGF-β mediates a shift from a TH17 profile to a TH1-like profile (3, 4). TH17 cell polarization is dependent on the transcription factor RORC2, the human homologue of the murine RORγt (3, 4, 5). In addition to IL-17, TH17 cells also produce IL-17F, IL-22, IL-21, IL-26, and the chemokine CCL20 (6, 7, 8), all of which may contribute to disease pathogenesis (9). A number of observations suggest that IL-17 may be important in rheumatoid arthritis (RA).3 IL-17 is found in RA synovial fluid and in the T cell-rich areas of RA synovial tissue (10, 11). Despite the observations by others (12), we found that TH17 cells were significantly increased in RA synovial fluid compared with RA or normal peripheral blood (13). A two-year prospective study analyzing RA synovial tissues demonstrated that IL-17 and TNF-α mRNA levels were synergistic prognostic factors for worse outcomes (14). The effects of IL-17 may be due to its ability to promote inflammation by inducing cytokines and chemokines (15, 16). Although the direct proinflammatory effects of IL-17 are often small when compared with those of IL-1β and TNF-α, IL-17 may enhance the effects of other cytokines. Using RA synovial tissue fibroblasts, IL-17 enhanced IL-1-mediated IL-6 and CCL20/MIP-3α production (17, 18) and the TNF-α-induced synthesis of IL-1, IL-6, IL-8, and CCL20 (18, 19). Therefore, a major role of IL-17 may be to amplify the effects of macrophage derived cytokines, and it may therefore be the missing link between T cells in RA joint and the effector phase of RA. The role of IL-17 in chemotaxis has been examined. The ectopic expression of IL-17 intra-articularly enhanced neutrophil migration into the joints of mice (20). In the rat airway, IL-17 mediates neutrophil recruitment via induction of IL-8 (21). Neutrophil chemotaxis caused by conditioned medium from IL-17-stimulated gastric epithelial cells was inhibited by a neutralizing Ab to IL-8 but not to IL-17, suggesting that IL-17 is unable to directly induce neutrophil chemotaxis (22). In contrast to its effects on neutrophils, little is known about the effect of IL-17 on the recruitment of monocytes. In the current study, therefore, we evaluated the role of IL-17 on monocyte migration. Our results demonstrate that IL-17 recruited monocytes into sponges implanted into SCID mice. In vitro, IL-17 was chemotactic for monocytes at the concentrations detected in the RA synovial fluid. Additionally, neutralizing Abs to IL-17 or to IL-17RA or RC significantly reduced RA synovial fluid-mediated monocyte migration. Taken together, these observations support the importance of IL-17 in recruiting monocytes to the RA synovial tissue. Hence, therapy directed against IL-17 may reduce inflammation by inhibiting monocyte migration into the joint.