Loganin Alleviates Gout Inflammation by Suppressing NLRP3 Inflammasome Activation and Mitochondrial Damage.

Nuri Choi,Yong-Yeon Cho,Han Chang Kang,Joo Hyeon Jang,Joo Young Lee,Hye Suk Lee,Gabsik Yang

doi:10.3390/molecules26041071

Nuri Choi, Yong-Yeon Cho + Show 5 more

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https://doi.org/10.3390/molecules26041071

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Abstract

Gout is a type of inflammatory arthritis caused by the deposition of monosodium uric acid (MSU) crystals in tissues. The etiology of gout is directly linked to the NLRP3 inflammasome, since MSU crystals are NLRP3 inflammasome activators. Therefore, we decided to search for a small-molecule inhibitor of the NLRP3 inflammasome for the prevention of gout inflammation. We found that loganin suppressed MSU crystals-induced caspase-1 (p20) and interleukin (IL)-1β production and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks formation in mouse primary macrophages, showing its ability to inhibit the NLRP3 inflammasome. In an air pouch inflammation model, oral administration of loganin to mice prevented MSU crystals-induced production of mature IL-1β and IL-18 in air pouch exudates, resulting in decreased neutrophil recruitment. Furthermore, oral administration of loganin suppressed MSU crystals-induced gout inflammation in a mouse foot gout model, which was accompanied by the inhibition of the NLRP3 inflammasome. Loganin blocked de novo synthesis of mitochondrial DNA in air pouches and foot tissues injected with MSU crystals. Consistently, loganin prevented MSU crystals-induced mitochondrial damage in macrophages, as it increased mitochondrial membrane potential and decreased the amount of mitochondrial reactive oxygen species. These data demonstrate that loganin suppresses NLRP3 inflammasome activation by inhibiting mitochondrial stress. These results suggest a novel pharmacological strategy to prevent gout inflammation by blocking NLRP3 inflammasome activation and mitochondrial dysfunction.

Highlights

The inflammasome is one of the pattern recognition receptors responding to pathogenassociated molecular patterns derived from invading pathogens [1,2]
Loganin treatment prevented the cleavage of procaspase-1 to caspase-1 (p20) and the degradation of pro-IL-1β to mature IL-1β induced by the monosodium uric acid (MSU) crystals in primary mouse macrophages, as determined by immunoblot analysis (Figure 1B)
The suppressive effects of loganin on the production of IL-1β and IL-18 and the MPO activity in air pouch exudates were similar in extent to those of colchicine. These results demonstrate in vivo suppressive effects of loganin on NLRP3 inflammasome activation induced by MSU crystals, which were well correlated with inhibition of inflammation

Summary

Introduction

The inflammasome is one of the pattern recognition receptors responding to pathogenassociated molecular patterns derived from invading pathogens [1,2]. The. NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1. NLRP3, acting as a sensor, is composed of an amino-terminal pyrin domain (PYD), a NACHT domain, and a carboxy-terminal leucine-rich repeat (LRR). ASC is composed of an amino-terminal PYD and a carboxy-terminal caspase recruitment domain (CARD). Caspase-1 has an amino-terminal CARD consisting of the catalytic domains p20 and p10. NLRP3 interacts with ASC through PYD–PYD association, while the interaction between ASC and pro-caspase-1 takes place via CARD–CARD interaction [4,5]. Activation of caspase-1 is achieved by proximity-induced autocatalytic activation, leading to the cleavage of the pro-forms of IL-1β and IL-18 to biologically active forms [6]. Active caspase-1 induces the degradation of gasdermin D (GSDMD)

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