CXCR2‐specific chemokines mediate leukotriene B₄–dependent recruitment of neutrophils to inflamed joints in mice with antigen‐induced arthritis

Abstract

Objective. To investigate the mechanism underlying neutrophil migration into the articular cavity in experimental arthritis and, by extension, human inflammatory synovitis.Methods. Antigen-induced arthritis (AIA) was generated in mice with methylated bovine serum albumin (mBSA). Migration assays and histologic analysis were used to evaluate neutrophil recruitment to knee joints. Levels of inflammatory mediators were measured by enzyme-linked immunosorbent assay. Antibodies and pharmacologic inhibitors were used in vivo to determine the role of specific disease mediators. Samples of synovial tissue and synovial fluid from rheumatoid arthritis (RA) or osteoarthritis patients were evaluated for CXCL1 and CXCL5 expression.Results. High levels of CXCL1, CXCL5, and leukotriene B 4 (LTB 4 ) were expressed in the joints of arthritic mice. Confirming their respective functional roles, repertaxin (a CXCR1/CXCR2 receptor antagonist), anti-CXCL1 antibody, anti-CXCL5 antibody, and MK886 (a leukotriene synthesis inhibitor) reduced mBSA-induced neutrophil migration to knee joints.Repertaxin reduced LTB 4 production in joint tissue, and neutrophil recruitment induced by CXCL1 or CXCL5 was inhibited by MK886, suggesting a sequential mechanism. Levels of both CXCL1 and CXCL5 were elevated in synovial fluid and were released in vitro by RA synovial tissues. Moreover, RA synovial fluid neutrophils stimulated with CXCL1 or CXCL5 released significant amounts of LTB 4 .Conclusion. Our data implicate CXCL1, CXCL5, and LTB 4 , acting sequentially, in neutrophil migration in AIA. Elevated levels of CXCL1 and CXCL5 in the synovial compartment of RA patients provide robust comparative data indicating that this mechanism plays a role in inflammatory joint disease. Together, these results suggest that inhibition of CXCL1, CXCL5, or LTB 4 may represent a potential therapeutic strategy in RA.

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

“…Intra-articular (tibiofemoral joint) injection of mBSA in mBSA-immunized mice induced a significant neutrophil migration to the articular cavity compared with non-immunized mice. The migration peaked 24 h after mBSA challenge (10 g/articular cavity) (18). mBSA-induced neutrophil recruitment was significantly inhibited by anti-IL-23 or anti-IL-17 antibodies (Fig.…”

“…However, the precise mechanism how the IL-23/IL-17 axis induces neutrophil migration in the articular context is unknown. We have reported previously that intra-articular (tibiofemoral joint) injection of antigen (methylated BSA, mBSA) induced a significant neutrophil migration to the articular cavity in immunized mice compared with non-immunized mice (18). Lipid mediators such as prostaglandins, particularly prostaglandin E 2 (PGE 2 ), are commonly found in the synovial fluid of RA patients and clearly are involved in the tissue inflammation observed in these subjects (19,20).…”

Anti-Inflammatory Effects of the Activation of the Angiotensin-(1–7) Receptor, Mas, in Experimental Models of Arthritis

“…The decreased accumulation of neutrophils and joint damage was associated with decreased local production of proinflammatory cytokines, including TNF-a and IL-1b, and neutrophil-active chemokines. It is well established that cytokines are responsible for the initiation and perpetuation of the inflammatory response in RA as well for the facilitation of neutrophil influx at sites of tissue injury (40,41). In this regard, TNF-a has a key role in the pathogenesis of RA (42) and facilitates the influx of leukocytes, which may in turn increase the local production of TNF-a (43).…”

Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

“…The chemoattractants CXCL1/KC, CXCL5/LIX and lymphotactin, which were also reduced in paws of anti-C5aR-treated mice 60 h after a single dose, have been demonstrated to be upregulated in both RA synovial tissue/fluid and other murine arthritis models [36,37]. In addition, it is suggested that lymphotactin can exert immunomodulatory effects through MMP release from synovial fibroblasts and cytokine release from macrophages in addition to its chemotactic properties [37].…”