期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：2
页码：506-511
DOI：10.1073/pnas.1414536112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceChronic low-grade inflammation plays a causative role in obesity-associated metabolic diseases. However, the mechanisms underlying chronicity of low-grade inflammation remain elusive. Herein, we identify inhibitor of {kappa}B kinase epsilon (IKBKE) as a new modulator of chronic inflammation in macrophages. We first show that IKBKE is clinically relevant in distinct tissues associated with metabolic diseases including obesity, nonalcoholic steatohepatitis, and atherosclerosis. In all cases, IKBKE expression predominates in macrophages and associates with chronic inflammation. In macrophages, IKBKE affects chronicity of inflammation by temporally limiting inflammasome priming. Both global IKBKE ablation and reconstitution with hematopoietic IKBKE reciprocally alters metaflammation in adipose tissue, liver, and the composition of advanced atherosclerotic plaques. These findings establish a nonpathogenic role for hematopoietic IKBKE in limiting inflammasome priming and metaflammation. 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.
