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

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

  • Circulation. 2015 Mar 24;131(12):1061-70. doi: 10.1161/CIRCULATIONAHA.114.013730.
Amna Abderrazak 1,  Dominique Couchie 1,  Dler Faieeq Darweesh Mahmood 1,  Rima Elhage 1,  Cécile Vindis 1,  Muriel Laffargue 1,  Véronique Matéo 1,  Berthold Büchele 1,  Monica Rubio Ayala 1,  Menna El Gaafary 1,  Tatiana Syrovets 1,  Mohamed-Naceur Slimane 1,  Bertrand Friguet 1,  Tamas Fulop 1,  Thomas Simmet 1,  Khadija El Hadri 1,  Mustapha Rouis 2
Affiliations

Affiliations

  • 1 From Sorbonne Universités, UPMC Université Paris 06, Biological Adaptation and Ageing-IBPS, Paris, France (A.A., D.C., D.F.D.M., R.E.H., B.F., K.E.H., M.R.); CNRS-UMR 8256, Paris, France (A.A., D.C., D.F.D.M., R.E.H., F.B., K.E.H., M.R.); Inserm U1164, Paris, France (A.A., D.C., D.F.D.M., R.E.H., B.F., K.E.H., M.R.); INSERM-UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France (C.V., M.L.); Centre de Recherche d'Immunologie et Maladies Infectieuses, CIMI-Paris UPMC UMRS CR7, INSERM U-1135, CNRS ERL 8255, Hôpital Pitié-Salpêtrière, Paris, France (V.M.); Ulm University, Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm, Germany (B.B., M.R.A., M.E.G., T.S., T.S.); Biochemistry Laboratory, Faculty of Medicine, TN-Monastir, Tunisia (M.-N.S.); and Centre de Recherche sur le Vieillissement, Service Gériatrique, Département de Médecine, Université de Sherbrooke, Sherbrooke, QC, Canada (T.F.).
  • 2 From Sorbonne Universités, UPMC Université Paris 06, Biological Adaptation and Ageing-IBPS, Paris, France (A.A., D.C., D.F.D.M., R.E.H., B.F., K.E.H., M.R.); CNRS-UMR 8256, Paris, France (A.A., D.C., D.F.D.M., R.E.H., F.B., K.E.H., M.R.); Inserm U1164, Paris, France (A.A., D.C., D.F.D.M., R.E.H., B.F., K.E.H., M.R.); INSERM-UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France (C.V., M.L.); Centre de Recherche d'Immunologie et Maladies Infectieuses, CIMI-Paris UPMC UMRS CR7, INSERM U-1135, CNRS ERL 8255, Hôpital Pitié-Salpêtrière, Paris, France (V.M.); Ulm University, Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm, Germany (B.B., M.R.A., M.E.G., T.S., T.S.); Biochemistry Laboratory, Faculty of Medicine, TN-Monastir, Tunisia (M.-N.S.); and Centre de Recherche sur le Vieillissement, Service Gériatrique, Département de Médecine, Université de Sherbrooke, Sherbrooke, QC, Canada (T.F.). [email protected].
PMID: 25613820 DOI: 10.1161/CIRCULATIONAHA.114.013730
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.

Keywords

arglabin-dimethylaminohydrochloride; atherosclerosis; cytokines; inflammasomes; inflammation.

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