Fucoidan Inhibits NLRP3 Inflammasome Activation by Enhancing p62/SQSTM1-Dependent Selective Autophagy to Alleviate Atherosclerosis.

Yufei Cheng,Xu Li,Shaonan Yang,Ruihua Yin,Xiaoyan Zhu,Jing Wang,Xudong Pan,Aijun Ma

doi:10.1155/2020/3186306

Abstract

NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation contributes to the progression of atherosclerosis, and autophagy inhibits inflammasome activation by targeting macrophages. We investigated whether fucoidan, a marine sulfated polysaccharide derived from brown seaweeds, could reduce NLRP3 inflammasome activation by enhancing sequestosome 1 (p62/SQSTM1)-dependent selective autophagy to alleviate atherosclerosis in high-fat-fed ApoE-/- mice with partial carotid ligation and differentiated THP-1 cells incubated with oxidized low-density lipoprotein (oxLDL). Fucoidan significantly ameliorated lipid accumulation, attenuated progression of carotid atherosclerotic plaques, deregulated the expression of NLRP3 inflammasome, autophagy receptor p62, and upregulated microtubule-associated protein light chain 3 (LC3)-II/I levels. Transmission electron microscopy and GFP-RFP-LC3 lentivirus transfection further demonstrated that fucoidan could activate autophagy. Mechanistically, fucoidan remarkably inhibited NLRP3 inflammasome activation, which was mostly dependent on autophagy. The inhibitory effects of fucoidan on NLRP3 inflammasome were enhanced by autophagy activator rapamycin (Rapa) and alleviated by autophagy inhibitor 3-methyladenine (3-MA). Fucoidan promoted the colocalization of NLRP3 and p62. Knockdown of p62 and ATG5 by small interfering RNA significantly reduced the inhibitory effects of fucoidan treatment on NLRP3 inflammasome. The data suggest that fucoidan can inhibit NLRP3 inflammasome activation by enhancing p62/SQSTM1-dependent selective autophagy to alleviate atherosclerosis.

Highlights

Ischemic stroke is a destructive cerebrovascular disease worldwide, with a high rate of death, disability, and recurrence [1]
During the development of atherosclerosis, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is inappropriately activated by cholesterol crystals, oxidized low-density lipoprotein, and abnormal hemodynamics, which results in massive inflammation [5]
The NLRP3 inflammasome is a cytosolic protein complex consisting of the NLRP3, apoptosis-associated speck-like protein (ASC), and protease caspase-1, which can cleave pro-IL-1β into mature IL-1β, aggravating the inflammatory response in atherosclerosis [6]

Summary

Introduction

Ischemic stroke is a destructive cerebrovascular disease worldwide, with a high rate of death, disability, and recurrence [1]. The main pathogenesis mechanism of ischemic stroke is carotid atherosclerosis, which is recognized as a chronic vascular inflammatory disease [2]. (NLRP3) inflammasome-dependent pathway is of great significance [4]. During the development of atherosclerosis, the NLRP3 inflammasome is inappropriately activated by cholesterol crystals, oxidized low-density lipoprotein (oxLDL), and abnormal hemodynamics, which results in massive inflammation [5]. The NLRP3 inflammasome is a cytosolic protein complex consisting of the NLRP3, apoptosis-associated speck-like protein (ASC), and protease caspase-1, which can cleave pro-IL-1β into mature IL-1β, aggravating the inflammatory response in atherosclerosis [6]. A genetic deficiency of NLRP3, ASC, or caspase-1 results in the low production of IL-1β and stabilizes atherosclerotic plaques

Methods

Results

Conclusion