Session Title: Cytokines, Mediators, and Gene Regulation II
Session Type: Abstract Submissions (ACR)
Background/Purpose: During attacks of acute gouty arthritis, monosodium urate (MSU) crystals elicit a potent neutrophilic inflammatory response in the affected joint, causing exquisite pain and often signs of systemic inflammation such as fever. IL-1β plays a critical role in the development of gouty arthritis, as demonstrated by studies of IL-1β and NLRP3 knockout mice and the effectiveness of IL-1 blockade in treating or preventing gouty arthritis in humans. However, mechanisms of neutrophil trafficking to sites of MSU crystal deposition during gouty inflammation have not been fully characterized, and our understanding of these pathways depends upon knowledge of the chemokine responses elicited by MSU crystals and their interface with chemotactic receptors on neutrophils. Deletion of the chemokine receptor CXCR2 in mice has been shown to impair initiation of MSU crystal-induced inflammation in the air pouch model of gouty arthritis, but the other major murine neutrophil chemotactic receptors – CCR1, BLT1 and C5a – have not been systematically studied.
Methods: Using the murine air pouch model of gouty arthritis, we have: (1) characterized the chemokine and cytokine profile of MSU crystal-induced inflammation using a multiplex bead immunoassay and (2) probed the time course of chemokine and cytokine production and neutrophil recruitment in CCR1-null, CXCR2-null, and CCR1-CXCR2 double knockout mice.
Results: While our findings confirm that CXCR2 is critical for the initiation of neutrophilic inflammation in MSU crystal-challenged air pouches, mice lacking CCR1 also fail to achieve the expected maximal neutrophilic response to MSU crystal challenge (at 8 hours post crystal challenge). Although CXCR2-null mice generate a very high level of KC and LIX (ligands for CXCR2) in the air pouch within 2 hours of MSU crystal challenge, MIP-1α and MIP-1β (ligands for CCR1), which typically appear 3-4 hours after crystal challenge, are not produced in these mice.
Conclusion: We propose that CXCR2 and CCR1 act sequentially to initiate and potentiate neutrophil infiltration during gouty inflammation, with CCR1 chemokine ligand generation being dependent upon neutrophils entering the inflammatory site in response to CXCR2 chemokine signals. These data broaden our understanding of coordinate chemokine-mediated neutrophil recruitment in a model of MSU crystal-induced arthritis and suggest that there may be a role for chemokine receptor modulation in the management of acute gouty arthritis in humans.
R. P. Friday,
T. K. Means,
C. D. Sadik,
A. D. Luster,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ccr1-potentiates-gouty-inflammation-following-initial-cxcr2-dependent-neutrophil-recruitment-to-sites-of-monosodium-urate-crystal-deposition-in-mice/