Objective: Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystal-induced IL-1β release contributes to inflammation in subcutaneous air pouch and peritoneal models of acute gout and pseudogout. However, consequences of IL-1 inhibition have not been explored in more clinically relevant models of crystal-induced arthritis. In this study, we developed a novel mouse model of acute gouty ankle arthritis, and used it to assess the effects of genetic deletion of IL-1R1 and of exogenous mIL-1 Trap (a high-affinity blocker of mouse IL-1α and IL-1β) on pain, synovitis, and systemic inflammatory biomarkers.
Methods: MSU crystals were injected into the mouse ankle joint, and pain and ankle swelling were measured over 4 days. The effects of IL-1 inhibition were determined in this model, as well as in the comparator models of crystal-induced peritonitis and subcutaneous air pouch inflammation.
Results: Both IL-1R1-null mice and mice pre-treated with mIL-1 Trap showed reduced neutrophil influx in MSU and CPPD crystal-induced peritonitis and air pouch models (p<0.05). In the ankle joint model, both IL-1R1 knockout mice and pre-treatment with mIL-1 Trap were associated with significant reductions in MSU crystal-induced elevations in hyperalgesia, inflammation, SAA, and the levels of multiple inflammatory cytokines and chemokines (p<0.05). In addition, we observed that administration of mIL-1 Trap following MSU crystal injection reduced established hyperalgesia and ankle swelling.
Conclusions: IL-1 inhibition both prevented and relieved pain and ankle joint inflammation in response to intra-articular MSU crystals in mice. Results suggested that IL-1 Trap has the potential to both prevent and treat gouty arthritis.