Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 2, Pages 506-511Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1414536112
Keywords
IKBKE; inflammasome; metaflammation; metabolic disease; immunometabolism
Categories
Funding
- British Heart Foundation Project [PG/10/38/28359]
- Gates Cambridge PhD Scholarship
- Wellcome Trust PhD Studentship
- National Institute for Health Research Cambridge Biomedical Research Centre
- INSERM
- University of Nice
- Programme Hospitalier de Recherche Clinique (Centre Hospitalier Universitaire of Nice)
- European Foundation for the Study of Diabetes/Lilly Fellowship
- French Government (National Research Agency) through Investments for the Future LABEX SIGNALIFE [ANR-11-LABX-0028-01]
- [RG/12/13/29853]
- [RG/13/14/30314]
- Biotechnology and Biological Sciences Research Council [BB/H013539/1, JF16994] Funding Source: researchfish
- British Heart Foundation [RG/13/14/30314, RG/12/13/29853, PG/10/38/28359, PG/13/25/30014] Funding Source: researchfish
- Medical Research Council [MC_UU_12012/5/B, G0400192, MC_UU_12012/5, MC_PC_13030, G0802051, MC_G0802535, MC_UU_12012/2, MC_UP_A090_1006, G0800784] Funding Source: researchfish
- BBSRC [BB/H013539/1] Funding Source: UKRI
- MRC [MC_G0802535, G0400192, G0802051, G0800784, MC_UU_12012/5, MC_UU_12012/2, MC_UP_A090_1006, MC_PC_13030] Funding Source: UKRI
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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 kappa B 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.
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