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, Sethi Jaswinder K
Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom;
Department of Clinical Biochemistry and University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom; Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Cambridge CB2 2QQ, United Kingdom;
Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):506-11. doi: 10.1073/pnas.1414536112. Epub 2014 Dec 24.
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.
肥胖会增加患危及生命的代谢性疾病的风险，这些疾病包括心血管疾病、脂肪肝疾病、糖尿病和癌症。遏制全球肥胖流行及其影响的努力部分已被证明是不成功的，原因是对这些慢性进展性疾病的了解有限。显然，低度慢性炎症，即代谢性炎症，是肥胖相关的2型糖尿病和动脉粥样硬化发病机制的基础。然而，维持慢性炎症并阻止炎症消退的机制却知之甚少。在此，我们表明κB激酶ε（IKBKE）抑制剂是一种新型调节因子，可在代谢性疾病和动脉粥样硬化期间限制慢性炎症。IKBKE与人类和小鼠组织以及动脉粥样硬化斑块中的巨噬细胞共定位，表明了其致病相关性。IKBKE基因敲除导致培养的巨噬细胞、肥厚性脂肪组织和高胆固醇血症小鼠肝脏中NLRP3炎性小体的启动增强和延长。这种改变的特征与急性期反应增强、胆固醇代谢失调和脂肪性肝炎有关。仅在造血细胞中恢复IKBKE足以逆转炎性小体启动升高和这些代谢特征。在晚期动脉粥样硬化斑块中，IKBKE的缺失和造血细胞的恢复改变了斑块组成。这些研究揭示了造血IKBKE的新作用：限制炎性小体启动和代谢性炎症。
