Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation

Significance Chronic 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 κB 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.