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

Arthritis Rheum. 2008 Jul;58(7):2030-40. doi: 10.1002/art.23597.

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 B4 (LTB4) 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 LTB4 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 LTB4.

Conclusion: Our data implicate CXCL1, CXCL5, and LTB4, 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 LTB4 may represent a potential therapeutic strategy in RA.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / immunology*
  • Chemokine CXCL1 / immunology
  • Chemokine CXCL5 / immunology
  • Chemotaxis, Leukocyte / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Knee Joint / immunology
  • Knee Joint / pathology
  • Leukotriene B4 / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils / immunology*
  • Receptors, Interleukin-8B / immunology*

Substances

  • CXCL1 protein, human
  • CXCL5 protein, human
  • Chemokine CXCL1
  • Chemokine CXCL5
  • Cxcl1 protein, mouse
  • Cxcl5 protein, mouse
  • Receptors, Interleukin-8B
  • Leukotriene B4