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

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.

• Authors: Yufei Cheng, Xudong Pan, Jing Wang, Xu Li, Shaonan Yang, Ruihua Yin, Aijun Ma, Xiaoyan Zhu
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2020 Pg. 3186306 ( 2020) ISSN: 1942-0994 [Electronic] United States
• PMID: 33505579 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Yufei Cheng et al.

Chemical References

• Autophagy-Related Protein 5
• Inflammasomes
• Lipoproteins, LDL
• MAP1LC3A protein, human
• Map1lc3b protein, mouse
• Microtubule-Associated Proteins
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Nlrp3 protein, mouse
• Polysaccharides
• SQSTM1 protein, human
• Sequestosome-1 Protein
• Sqstm1 protein, mouse
• oxidized low density lipoprotein
• 3-methyladenine
• fucoidan
• Adenine
• Sirolimus

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Atherosclerosis (metabolism)
• Autophagosomes (drug effects, ultrastructure)
• Autophagy (drug effects)
• Autophagy-Related Protein 5 (genetics, metabolism)
• Gene Knockdown Techniques
• Humans
• Inflammasomes (drug effects, metabolism)
• Lipid Metabolism (drug effects)
• Lipoproteins, LDL (pharmacology)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Electron, Transmission
• Microtubule-Associated Proteins (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Plaque, Atherosclerotic (drug therapy, metabolism)
• Polysaccharides (pharmacology)
• Sequestosome-1 Protein (genetics, metabolism)
• Sirolimus (pharmacology)