Rhein, An Anthraquinone Drug, Suppresses the NLRP3 Inflammasome and Macrophage Activation in Urate Crystal-Induced Gouty Inflammation

Abstract

Rhein, an anthraquinone drug, is a widely used traditional Chinese medicine. Rhein is a major bioactive metabolite of diacerein which has been approved for treating osteoarthritis with a good safety profile in humans. Gouty arthritis is an inflammatory disease characterized by urate crystal-induced NLRP3 inflammasome activation with up-regulated caspase-1 protease and IL-1[Formula: see text] in macrophages. Inhibition of the NLRP3 inflammasome formation has been considered as a potential therapeutic avenue for treating or preventing many inflammatory diseases. This study aimed to evaluate the anti-inflammatory effects of rhein on gouty arthritis. Rhein within the physiological levels of humans showed no toxicity on the cell viability and differentiation, but significantly decreased the production of IL-1[Formula: see text], TNF-[Formula: see text] and caspase-1 protease in urate crystal-activated macrophages. Compared to medium controls, rhein at the therapeutic concentration (2.5[Formula: see text][Formula: see text]g/mL) effectively inhibited IL-1[Formula: see text] production by 47% ([Formula: see text]). Rhein did not affect the mRNA levels of CASP1, NLRP3 and ASC, but suppressed the protein expression and enzyme activity of caspase-1. Immunofluorescence confocal microscopy further revealed that rhein suppressed the aggregation of ASC speck and inhibited the formation of NLRP3 inflammasome. Rhein of 5[Formula: see text][Formula: see text]g/mL significantly decreased the ASC speck to 36% ([Formula: see text]), and reduced the NLRP3 aggregates to 37.5% ([Formula: see text]). Our data demonstrate that rhein possesses pharmacological activity to suppress caspase-1 protease activity and IL-1[Formula: see text] production by interfering with the formation of NLRP3 multiprotein complex. These results suggest that rhein has therapeutic potential for treating NLRP3 inflammasome-mediated diseases such as gouty arthritis.

Anti-inflammatory Effects and Mechanisms of Rhein, an Anthraquinone Compound, and Its Applications in Treating Arthritis: A Review

“…Chang et al [26] evaluated the anti-inflammatory activities of rhein on GA and found that it significantly decreases IL-1β production induced by urate crystal by interrupting NLRP3 formation and suppressing caspase 1 (CASP1) protease activity within the physiological levels. In addition, rhein inhibits the transport activity of the renal organic anion transporter (OAT), resulting in the reduction of uric acid re-uptake.…”

“…Medicinal plants play a vital role as sources of active anti-inflammatory ingredients in the prevention of various inflammatory diseases. Rhein, a bioactive constituent of anthraquinone, has been well recognized for its excellent anti-inflammatory activities and therapeutic effects on arthritis [26]. A growing body of researches have demonstrated that rhein exhibits anti-inflammatory activities by inhibiting cytokines [27,28] and interleukins [29] which cause inflammatory responses and metabolic abnormalities, stimulates the formation of cartilage matrix material and promotes cartilage repair to remodel joint structures [30,31].…”

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

“…[ 82 ] Rhein interfered with the formation of NLRP3 inflammasome by inhibiting caspase‐1 protease activity and IL‐1β production, which suggested that rhein has therapeutic potential for treating NLRP3 inflammasome‐mediated diseases. [ 83 ]…”

Anti-inflammatory Mechanism of Rhein in Treating Asthma Based on Network Pharmacology

“…MAPK14, EGFR, EERB2, TNFRSF1A, etc., are the main targets of the anti-in ammatory effects of rhein. Rhein can directly act on EGFR, MAPK14, EERB2, and TNFRSF1A and can also indirectly act on other targets to exert its anti-in ammatory effects [16,17,18,19].…”