15d-PGJ 2 -loaded nanocapsules ameliorate experimental gout arthritis by reducing pain and inflammation in a PPAR-gamma-sensitive manner in mice

Gout arthritis (GA) is a painful inflammatory disease in response to monosodium urate (MSU) crystals in the joints. 15deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) is a natural activator of PPAR-γ with analgesic, anti-inflammatory, and pro-resolution properties. Thus, we aimed to evaluate the effect and mechanisms of action of 15d-PGJ 2 nanocapsules (NC) in the model of GA in mice, since a reduction of 33-fold in the dose of 15d-PGJ 2 has been reported. Mice were treated with 15d-PGJ 2 -loaded NC, inert NC, free 15d-PGJ 2 (without NC), or 15d-PGJ 2 -loaded NC+ GW9662, a PPAR-γ inhibitor. We show that 15d-PGJ 2 -loaded NC provided analgesic effect in a dose that the free 15d-PGJ 2 failed to inhibiting pain and inflammation. Hence, 15d-PGJ 2 -loaded NC reduced MSU-induced IL-1β, TNF-α, IL-6, IL-17, and IL-33 release and oxidative stress. Also, 15d-PGJ 2 -loaded NC decreased the maturation of IL-1β in LPS-primed BMDM triggered by MSU. Further, 15d-PGJ 2 -loaded NC decreased the expression of the components of the inflammasome Nlrp3 , Asc , and Pro-caspase-1 , as consequence of inhibiting NF-κB activation. All effects were PPAR-γ-sensitive. Therefore, we demonstrated that 15d-PGJ 2 -loaded NC present analgesic and anti-inflammatory properties in a PPAR-γ-dependent manner inhibiting IL-1β release and NF-κB activation in GA. Concluding, 15d-PGJ 2 -loaded NC ameliorates MSU-induced GA in a PPAR-γ-sensitive manner.