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-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a natural activator of PPAR-gamma 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-PGJ2 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-gamma 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-1 beta, TNF-alpha, IL-6, IL-17, and IL-33 release and oxidative stress. Also, 15d-PGJ(2)-loaded NC decreased the maturation of IL-1 beta 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-kappa B activation. All effects were PPAR-gamma-sensitive. Therefore, we demonstrated that 15d-PGJ(2)-loaded NC present analgesic and anti-inflammatory properties in a PPAR-gamma-dependent manner inhibiting IL-1 beta release and NF-kappa B activation in GA. Concluding, 15d-PGJ(2)-loaded NC ameliorates MSU-induced GA in a PPAR-gamma-sensitive manner.