Abstract
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.
Highlights
Gallic acid (3,4,5-trihydroxybenzoic acid) is a phenolic acid widely distributed in various foods and herbs such as tea, grapes, guava, mulberry, pomegranate, cynomorium, and peony [1]
We investigated the influence of gallic acid on NLRP3 inflammasome activation and pyroptosis in macrophages, and its effect on gouty arthritis mice
Our results suggested that gallic acid enhances the nuclear factor E2-related factor 2 (Nrf2) signaling to suppress NLRP3 inflammasome activation and pyroptosis and alleviate NLRP3dependent gouty arthritis
Summary
Gallic acid (3,4,5-trihydroxybenzoic acid) is a phenolic acid widely distributed in various foods and herbs such as tea, grapes, guava, mulberry, pomegranate, cynomorium, and peony [1]. Gallic acid is commonly used as a dietary supplement or additive and displays a range of pharmacological activities, including in the treatment of inflammatory bowel disease, cardiovascular diseases, diabetes, and tumors [2, 3]. These activities are closely linked to its antiinflammatory and antioxidant properties [1, 4]. Gallic acid can elicit anti-inflammatory effects by alleviating lipopolysaccharide (LPS)-induced neuroinflammation and oxidative stress [6]. Gallic acid can inhibit MAPK/NF-kB and enhance the activity of the AKT/AMPK/Nrf pathway, further indicating its anti-inflammatory and antioxidant properties [7]. The correlation between the anti-inflammatory and antioxidant effects of gallic acid remains unclear
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