Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation.

Autor: Patel MN; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;, Bernard WG; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom; Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2QQ, United Kingdom;, Milev NB; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;, Cawthorn WP; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;, Figg N; Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2QQ, United Kingdom;, Hart D; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;, Prieur X; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;, Virtue S; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;, Hegyi K; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;, Bonnafous S; Team 8, Hepatic Complications in Obesity, INSERM, U1065, Nice, F-06204, Cedex 3, France; Digestive Center, Centre Hospitalier Universitaire of Nice, Nice, F-06202, Cedex 3, France; Faculty of Medecine, University of Nice-Sophia-Antipolis, Nice, F-06107, Cedex 2, France;, Bailly-Maitre B; Team 8, Hepatic Complications in Obesity, INSERM, U1065, Nice, F-06204, Cedex 3, France; Digestive Center, Centre Hospitalier Universitaire of Nice, Nice, F-06202, Cedex 3, France; Faculty of Medecine, University of Nice-Sophia-Antipolis, Nice, F-06107, Cedex 2, France;, Chu Y; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom; MRC Human Nutrition Research Elsie Widdowson Laboratory, Cambridge CB1 9NL, United Kingdom;, Griffin JL; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom; MRC Human Nutrition Research Elsie Widdowson Laboratory, Cambridge CB1 9NL, United Kingdom;, Mallat Z; Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2QQ, United Kingdom;, Considine RV; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; and., Tran A; Team 8, Hepatic Complications in Obesity, INSERM, U1065, Nice, F-06204, Cedex 3, France; Digestive Center, Centre Hospitalier Universitaire of Nice, Nice, F-06202, Cedex 3, France; Faculty of Medecine, University of Nice-Sophia-Antipolis, Nice, F-06107, Cedex 2, France;, Gual P; Team 8, Hepatic Complications in Obesity, INSERM, U1065, Nice, F-06204, Cedex 3, France; Digestive Center, Centre Hospitalier Universitaire of Nice, Nice, F-06202, Cedex 3, France; Faculty of Medecine, University of Nice-Sophia-Antipolis, Nice, F-06107, Cedex 2, France;, Takeuchi O; Department of Host Defense, Research Institute for Microbial Diseases, Osaka University Yamada-oka, Suita, Osaka 565-0871, Japan., Akira S; Department of Host Defense, Research Institute for Microbial Diseases, Osaka University Yamada-oka, Suita, Osaka 565-0871, Japan., Vidal-Puig A; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;, Bennett MR; Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2QQ, United Kingdom;, Sethi JK; Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom; j.sethi@oxon.org.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2015 Jan 13; Vol. 112 (2), pp. 506-11. Date of Electronic Publication: 2014 Dec 24.
DOI: 10.1073/pnas.1414536112
Abstrakt: Obesity increases the risk of developing life-threatening metabolic diseases including cardiovascular disease, fatty liver disease, diabetes, and cancer. Efforts to curb the global obesity epidemic and its impact have proven unsuccessful in part by a limited understanding of these chronic progressive diseases. It is clear that low-grade chronic inflammation, or metaflammation, underlies the pathogenesis of obesity-associated type 2 diabetes and atherosclerosis. However, the mechanisms that maintain chronicity and prevent inflammatory resolution are poorly understood. Here, we show that inhibitor of κB kinase epsilon (IKBKE) is a novel regulator that limits chronic inflammation during metabolic disease and atherosclerosis. The pathogenic relevance of IKBKE was indicated by the colocalization with macrophages in human and murine tissues and in atherosclerotic plaques. Genetic ablation of IKBKE resulted in enhanced and prolonged priming of the NLRP3 inflammasome in cultured macrophages, in hypertrophic adipose tissue, and in livers of hypercholesterolemic mice. This altered profile associated with enhanced acute phase response, deregulated cholesterol metabolism, and steatoheptatitis. Restoring IKBKE only in hematopoietic cells was sufficient to reverse elevated inflammasome priming and these metabolic features. In advanced atherosclerotic plaques, loss of IKBKE and hematopoietic cell restoration altered plaque composition. These studies reveal a new role for hematopoietic IKBKE: to limit inflammasome priming and metaflammation.
Databáze: MEDLINE
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