Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation

Patel, Meghana N., Bernard, William G., Milev, Nikolay B., Cawthorn, William P., Figg, Nichola, Hart, Dan, Prieur, Xavier, Virtue, Sam, Hegyi, Krisztina, Bonnafous, Stephanie, Bailly-Maitre, Beatrice, Chu, Yajing, Griffin, Julian L., Mallat, Ziad, Considine, Robert V., Tran, Albert, Gual, Philippe, Takeuchi, Osamu, Akira, Shizuo, Vidal-Puig, Antonio, Bennett, Martin R. and Sethi, Jaswinder K. (2015) Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation. Proceedings of the National Academy of Sciences of the United States of America, 112 (2), 506-511. (doi:10.1073/pnas.1414536112).

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.

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Contributors

Author: Jaswinder K. Sethi

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