Autophagy induced by PP121 alleviates MSU crystal-induced acute gouty arthritis via inhibition of the NLRP3 inflammasome

Acute gouty arthritis (AGA) is a frequent self-limiting inflammatory condition produced by the deposition of monosodium urate (MSU) crystals in the joints and periarticular tissues of patients with hyperuricemia. However, no effective interventional measures currently exist for AGA. Pyroptosis, a kind of pro-inflammatory programmed cell death, plays a crucial role in MSU crystal-induced inflammation and represents a potential treatment target for AGA. Therefore, we determined the therapeutic benefits and mechanism of PP121, a pyroptosis-related compound, on AGA. First, we injected an MSU crystal solution intra-articularly into the left foot pad of C57BL/6 mice to create an AGA mouse model. Subsequent treatment with PP121 substantially decreased tissue damage, pro-inflammatory cytokine release, and inflammatory cell infiltration caused by MSU crystals in the ankle joint. Consistent with these observations, the beneficial effects of PP121 on AGA were cancelled in Beclin1+/-(Becn1+/-) mice. Furthermore, after PP121 treatment, super-resolution microscopy revealed a strong relationship between lysosome-connected membrane protein/light chain 3 positive vesicles and the nucleotide-binding domain of leucine-rich family pyrin domain-containing 3 (NLPR3), demonstrating that PP121 promotes phagocytosis of the NLPR3 inflammasome. In summary, PP121-mediated autophagy can improve degradation of the NLRR3 inflammasome in AGA, which suggests the therapeutic potential of PP121 in AGA.