Anti-inflammatory and antiatherogenic effects of the NLRP3 inflammasome inhibitor arglabin in ApoE2.Ki mice fed a high-fat diet.

Abstract

BACKGROUND:

This study was designed to evaluate the effect of arglabin on the NLRP3 inflammasome inhibition and atherosclerotic lesion in ApoE2Ki mice fed a high-fat Western-type diet.

METHODS AND RESULTS:

Arglabin was purified, and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, interleukin (IL)-1β and IL-18, but not IL-6 and IL-12, production in lipopolysaccharide and cholesterol crystal-activated cultured mouse peritoneal macrophages, with a maximum effect at ≈50 nmol/L and EC50 values for both cytokines of ≈ 10 nmol/L. Lipopolysaccharide and cholesterol crystals did not induce IL-1β and IL-18 production in Nlrp3(-/-) macrophages. In addition, arglabin activated autophagy as evidenced by the increase in LC3-II protein. Intraperitoneal injection of arglabin (2.5 ng/g body weight twice daily for 13 weeks) into female ApoE2.Ki mice fed a high-fat diet resulted in a decreased IL-1β plasma level compared with vehicle-treated mice (5.2±1.0 versus 11.7±1.1 pg/mL). Surprisingly, arglabin also reduced plasma levels of total cholesterol and triglycerides to 41% and 42%, respectively. Moreover, arglabin oriented the proinflammatory M1 macrophages into the anti-inflammatory M2 phenotype in spleen and arterial lesions. Finally, arglabin treatment markedly reduced the median lesion areas in the sinus and whole aorta to 54% (P=0.02) and 41% (P=0.02), respectively.

CONCLUSIONS:

Arglabin reduces inflammation and plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE2.Ki mice fed a high-fat diet. Consequently, a marked reduction in atherosclerotic lesions was observed. Thus, arglabin may represent a promising new drug to treat inflammation and atherosclerosis.

• Authors: Amna Abderrazak, Dominique Couchie, Dler Faieeq Darweesh Mahmood, Rima Elhage, Cécile Vindis, Muriel Laffargue, Véronique Matéo, Berthold Büchele, Monica Rubio Ayala, Menna El Gaafary, Tatiana Syrovets, Mohamed-Naceur Slimane, Bertrand Friguet, Tamas Fulop, Thomas Simmet, Khadija El Hadri, Mustapha Rouis
• Journal: Circulation (Circulation) Vol. 131 Issue 12 Pg. 1061-70 (Mar 24 2015) ISSN: 1524-4539 [Electronic] United States
• PMID: 25613820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Anti-Inflammatory Agents
• Apolipoprotein E2
• Carrier Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Sesquiterpenes
• Sesquiterpenes, Guaiane
• arglabin

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Apolipoprotein E2 (deficiency)
• Atherosclerosis (blood, drug therapy, etiology)
• Carrier Proteins (antagonists & inhibitors)
• Diet, High-Fat (adverse effects)
• Female
• Inflammasomes (antagonists & inhibitors, metabolism)
• Macrophages (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Sesquiterpenes (pharmacology, therapeutic use)
• Sesquiterpenes, Guaiane
• Treatment Outcome