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.he metabolic syndrome is defined by the coexistence of central obesity, deregulated carbohydrate, and lipid metabolism and/or hypertension. Collectively these features increase the risk of developing type 2 diabetes, nonalcoholic fatty liver diseases, and atherosclerosis. These metabolic diseases have additional features in common; they are chronic disorders characterized by a state of persistent inflammation and tissue remodeling. In particular, chronic low-grade inflammation or "metaflammation" is now established as an important causative factor driving metabolic disease. Much progress has been made in our understanding of how metabolic stress or overnutrition induces metaflammation. However, the molecules involved in maintaining chronicity of low-grade inflammation remain unclear.As specialized mediators of host defense, macrophages express danger-sensing pattern recognition receptors (PRRs) that include transmembrane receptors of the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) superfamily and intracellular cytosolic receptors such as RIG-I-like receptors and nucleotide-binding oligomerization domain (NOD)-like receptors (1, 2). Numerous TLR/IL-1Rs and their downstream mediators have been implicated in the pathogenesis of obesity-associated diabetes (3, 4), fatty liver disease (5, 6), and atherosclerosis (7,8). In some cases, putative nonmicrobial, host-derived sterile ligands have also been identified. For example, TLR4 is a putative sensor for dietary saturated fatty acids (SF...

Inflammasome Priming in Sterile Inflammatory Disease

“…This work shows that induction of IKKi parallels priming of the NLRP3 inflammasome in PRR-activated mouse macrophages in vitro [83] . Once induced, it limits the chronicity of NLRP3 inflammasome priming and the subsequent inflammatory response in this proatherogenic and hyperlipidemic mouse model [83] .…”

“…Ablation of NF-κB family kinase IKKi in the hyperlipidemic, proatherogenic Apoe −/− mouse model has reportedly led to increased NLRP3 inflammasome priming [83] . This work shows that induction of IKKi parallels priming of the NLRP3 inflammasome in PRR-activated mouse macrophages in vitro [83] .…”

TNF‐α Upregulates IKKε Expression via the Lin28B/let‐7a Pathway to Induce Catecholamine Resistance in Adipocytes

“…Two other studies have indicated that IKKε produces catecholamine resistance in obesity via activating phosphodiesterase 3B to reduce cyclic AMP levels, further inhibiting the phosphorylation of HSL (10,14). Interestingly, published data have indicated that when male mice were fed an obesogenic diet, deficiency of IKKε did not alter or prevent the development of obesity (12,23). This contrasts with and challenges the suggestion that IKKε ablation alters energy expenditure in obesity, as reported by Chiang et al (11).…”

Inflammasomes: mechanism of action, role in disease, and therapeutics

“…Recently, it was shown that the lack of inhibitor of κB kinase epsilon (IKBKE), a downstream mediator of TLR and cytokine signals, in ApoE-deficient mice fed a Western-type diet (high in saturated fat) caused enhanced expression of inflammasome-related genes and low-grade chronic inflammation 124 . Hence, IKBKE functions as an endogenous negative regulator of the NLRP3 inflammasome under an obesity-inducing condition.…”