Epigallocatechin-3-Gallate Prevents Acute Gout by Suppressing NLRP3 Inflammasome Activation and Mitochondrial DNA Synthesis.

Hye Eun Lee,Hye Suk Lee,Joo Young Lee,Han Chang Kang,Yong-Yeon Cho,Youn Bum Park,Gabsik Yang

doi:10.3390/molecules24112138

Abstract

Gout is a chronic inflammatory disease evoked by the deposition of monosodium urate (MSU) crystals in joint tissues. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is responsible for the gout inflammatory symptoms induced by MSU crystals. We investigated whether epigallocatechin-3-gallate (EGCG) suppresses the activation of the NLRP3 inflammasome, thereby effectively preventing gouty inflammation. EGCG blocked MSU crystal-induced production of caspase-1(p10) and interleukin-1β in primary mouse macrophages, indicating its suppressive effect on the NLRP3 inflammasome. In an acute gout mouse model, oral administration of EGCG to mice effectively alleviated gout inflammatory symptoms in mouse foot tissue injected with MSU crystals. The in vivo suppressive effects of EGCG correlated well with the suppression of the NLRP3 inflammasome in mouse foot tissue. EGCG inhibited the de novo synthesis of mitochondrial DNA as well as the production of reactive oxygen species in primary mouse macrophages, contributing to the suppression of the NLRP3 inflammasome. These results show that EGCG suppresses the activation of the NLRP3 inflammasome in macrophages via the blockade of mitochondrial DNA synthesis, contributing to the prevention of gouty inflammation. The inhibitory effects of EGCG on the NLRP3 inflammasome make EGCG a promising therapeutic option for NLRP3-dependent diseases such as gout.

Highlights

Gout is a relatively common inflammatory arthritis that can cause pain in the joints and seriously impair the quality of life of a patient
We investigated whether EGCG blocks the activation of the NLRP3 inflammasome induced by various activators in primary mouse macrophages
The inhibitory effects of on gouty inflammation and neutrophil recruitment in foot tissues injected with monosodium uric acid (MSU) crystals

Summary

Introduction

Gout is a relatively common inflammatory arthritis that can cause pain in the joints and seriously impair the quality of life of a patient. Crystals in joints is a key factor in the initiation and development of gout [2]. Accumulating evidence indicates that the MSU crystals-induced inflammatory responses and gout pathogenesis are dependent on interleukin (IL)-1β [3]. It is well established that the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing. 3 (NLRP3) inflammasome senses MSU crystal deposition, subsequently activating the downstream immune signals and inducing the production of IL-1β [3]. The NLRP3 inflammasome is a multiprotein complex consisting of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) as an adaptor, and pro-caspase-1 as an effector enzyme [4].

Methods

Results

Conclusion