Myeloid cell TBK1 restricts inflammatory responses
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
119
Journal Issue
4
Date Issued
2022
Author(s)
Gao, Tianxiao
Liu, Ting
Zhang, Lingyun
Joo, Donghyun
Xie, Xiaoping
Zhu, Lele
Li, Yanchuan
Cheng, Xuhong
Sun, Shao-Cong
Abstract
Proinflammatory 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.
Subjects
TBK1; fatty liver disease; inflammation; macrophages; metabolic disorders
SDGs
Publisher
NATL ACAD SCIENCES
Type
journal article