Abstract
Gouty arthritis results from the generation of uric acid crystals within the joints. These uric acid crystals activate the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, which is involved in chronic inflammatory diseases, including gouty arthritis. This study identified the polyenylpyrrole derivative 4-hydroxy auxarconjugatin B (4-HAB), a novel autophagy inducer, which attenuated uric acid crystals-mediated activation of the NLRP3 inflammasome in vitro and in vivo. 4-HAB dose-dependently reduced the release of interleukin (IL)-1β, IL-18, active caspase-1 and apoptosis-associated speck-like protein (ASC) in uric acid crystals-activated macrophages. In a mechanistic study, 4-HAB was shown to inhibit uric acid crystals-induced mitochondrial damage, lysosomal rupture and ASC oligomerization. Additionally, 4-HAB inhibited the NLRP3 inflammasome through Sirt1-dependent autophagy induction. Furthermore, the anti-inflammatory properties of 4-HAB were confirmed in a mouse model of uric acid crystals-mediated peritonitis by the reduced levels of neutrophil influx, IL-1β, active caspase-1, IL-6 and MCP-1 in lavage fluids. In conclusion, 4-HAB attenuates gouty inflammation, in part by attenuating activation of the NLRP3 inflammasome through the Sirt1/autophagy induction pathway.
Highlights
Macrophages are one of the important immune cells that play an essential role in the host defence system; excessive inflammation caused by over reactive macrophages and leads to inflammatory diseases or autoimmune disorders [1]
Using mitochondria-specific labels that distinguished intact (MitoTracker Deep Red) and total (MitoTracker Green) mitochondria, we found that MSU crystals treatment resulted in a reduction in MitoTracker Deep Red staining, indicating obvious mitochondrial damage, but this effect was abolished by 4-hydroxy auxarconjugatin B (4-HAB) (Figure 2A)
Uptake of MSU crystals by macrophages induces proinflammatory cytokine and chemokine productions, which leads to the further recruitment of immune cells into the joint and escalates the inflammation [25,26]
Summary
Macrophages are one of the important immune cells that play an essential role in the host defence system; excessive inflammation caused by over reactive macrophages and leads to inflammatory diseases or autoimmune disorders [1]. As the NLRP3 inflammasome recognizes and responses to the board range medicinally relevant stimuli, dysregulated NLRP3 inflammasome activation participates many human inflammatory diseases, including gout, type II diabetes, atherosclerosis and neurodegenerative disorders [5]. The current therapeutic strategies for NLRP3-associated complications are based on the non-steroidal anti-inflammatory drugs, colchicines or glucocorticoids, which are not satisfactory and cause significant side effects [6]. The development of a novel NLRP3 inflammasome inhibitor is a therapeutic option to counteract dysregulated NLRP3-associated diseases. As part of our efforts is to identify novel NLRP3 inflammasome inhibitors [11,12,13,14,15] and based on the known anti-inflammatory effects of 4-HAB, we hypothesized that 4-HAB can inhibit the NLRP3 inflammasome
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