title: Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation.
abstract: 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.
authors.affiliation: Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Meghana N
authors.initials: MN
authors.lastname: Patel
authors.affiliation: 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;
authors.forename: William G
authors.initials: WG
authors.lastname: Bernard
authors.affiliation: Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Nikolay B
authors.initials: NB
authors.lastname: Milev
authors.affiliation: Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: William P
authors.initials: WP
authors.lastname: Cawthorn
authors.affiliation: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2QQ, United Kingdom;
authors.forename: Nichola
authors.initials: N
authors.lastname: Figg
authors.affiliation: Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Dan
authors.initials: D
authors.lastname: Hart
authors.affiliation: Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Xavier
authors.initials: X
authors.lastname: Prieur
authors.affiliation: Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Sam
authors.initials: S
authors.lastname: Virtue
authors.affiliation: Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Krisztina
authors.initials: K
authors.lastname: Hegyi
authors.affiliation: 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;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bonnafous
authors.affiliation: 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;
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bailly-Maitre
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom; MRC Human Nutrition Research Elsie Widdowson Laboratory, Cambridge CB1 9NL, United Kingdom;
authors.forename: Yajing
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom; MRC Human Nutrition Research Elsie Widdowson Laboratory, Cambridge CB1 9NL, United Kingdom;
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2QQ, United Kingdom;
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; and.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Considine
authors.affiliation: 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;
authors.forename: Albert
authors.initials: A
authors.lastname: Tran
authors.affiliation: 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;
authors.forename: Philippe
authors.initials: P
authors.lastname: Gual
authors.affiliation: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.affiliation: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2QQ, United Kingdom;
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
authors.affiliation: Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom; j.sethi@oxon.org.
authors.forename: Jaswinder K
authors.identifier: http://orcid.org/0000-0003-4157-0475
authors.initials: JK
authors.lastname: Sethi
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D005260:Female; D006413:Hematopoietic System / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058226:Plaque, Atherosclerotic / Q000209:etiology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D012333:RNA, Messenger; D051550:I-kappa B Kinase; C496565:IKBKE protein, human; C496566:Ikbke protein, mouse
keywords: IKBKE; immunometabolism; inflammasome; metabolic disease; metaflammation