Gao, TianxiaoTianxiaoGaoLiu, TingTingLiuChun-Jung KoZhang, LingyunLingyunZhangJoo, DonghyunDonghyunJooXie, XiaopingXiaopingXieZhu, LeleLeleZhuLi, YanchuanYanchuanLiCheng, XuhongXuhongChengSun, Shao-CongShao-CongSun2022-08-082022-08-0820220027-84241091-6490https://scholars.lib.ntu.edu.tw/handle/123456789/616298Proinflammatory cytokine production by innate immune cells plays a crucial role in inflammatory diseases, but the molecular mechanisms controlling the inflammatory responses are poorly understood. Here, we show that TANK-binding kinase 1 (TBK1) serves as a vital regulator of proinflammatory macrophage function and protects against tissue inflammation. Myeloid cell-conditional Tbk1 knockout (MKO) mice spontaneously developed adipose hypertrophy and metabolic disorders at old ages, associated with increased adipose tissue M1 macrophage infiltration and proinflammatory cytokine expression. When fed with a high-fat diet, the Tbk1-MKO mice also displayed exacerbated hepatic inflammation and insulin resistance, developing symptoms of nonalcoholic steatohepatitis. Furthermore, myeloid cell-specific TBK1 ablation exacerbates inflammation in experimental colitis. Mechanistically, TBK1 functions in macrophages to suppress the NF-κB and MAP kinase signaling pathways and thus attenuate induction of proinflammatory cytokines, particularly IL-1β. Ablation of IL-1 receptor 1 (IL-1R1) eliminates the inflammatory symptoms of Tbk1-MKO mice. These results establish TBK1 as a pivotal anti-inflammatory mediator that restricts inflammation in different disease models.enTBK1; fatty liver disease; inflammation; macrophages; metabolic disorders[SDGs]SDG3journal article10.1073/pnas.2107742119350749212-s2.0-85123904681WOS:000758465600006https://api.elsevier.com/content/abstract/scopus_id/85123904681https://www.scopus.com/inward/record.uri?eid=2-s2.0-85123904681&doi=10.1073%2fpnas.2107742119&partnerID=40&md5=d25d2db1de6518774537f69795de3a46