Gallic acid is an active
phenolic acid widely distributed in plants, and there is compelling evidence to prove its anti-inflammatory effects. NLRP3
inflammasome dysregulation is closely linked to many inflammatory diseases. However, how
gallic acid affects the NLRP3
inflammasome remains unclear. Therefore, in the present study, we investigated the mechanisms underlying the effects of
gallic acid on the NLRP3
inflammasome and pyroptosis, as well as its effect on
gouty arthritis in mice. The results showed that
gallic acid inhibited
lactate dehydrogenase (LDH) release and pyroptosis in
lipopolysaccharide (LPS)-primed and
ATP-,
nigericin-, or
monosodium urate (MSU) crystal-stimulated macrophages. Additionally,
gallic acid blocked NLRP3
inflammasome activation and inhibited the subsequent activation of caspase-1 and secretion of IL-1β.
Gallic acid exerted its inhibitory effect by blocking NLRP3-NEK7 interaction and ASC oligomerization, thereby limiting
inflammasome assembly. Moreover,
gallic acid promoted the expression of
nuclear factor E2-related factor 2 (Nrf2) and reduced the production of mitochondrial ROS (mtROS). Importantly, the inhibitory effect of
gallic acid could be reversed by treatment with the Nrf2 inhibitor ML385. NRF2
siRNA also abolished the inhibitory effect of
gallic acid on IL-1β secretion. The results further showed that
gallic acid could mitigate MSU-induced joint swelling and inhibit IL-1β and
caspase 1 (p20) production in mice. Moreover,
gallic acid could moderate MSU-induced macrophages and neutrophils migration into joint
synovitis. In summary, we found that
gallic acid suppresses ROS generation, thereby limiting NLRP3
inflammasome activation and pyroptosis dependent on Nrf2 signaling, suggesting that
gallic acid possesses therapeutic potential for the treatment of
gouty arthritis.