| First Author | Gao T | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 4 | PubMed ID | 35074921 |
| Mgi Jnum | J:320662 | Mgi Id | MGI:6870486 |
| Doi | 10.1073/pnas.2107742119 | Citation | Gao T, et al. (2022) Myeloid cell TBK1 restricts inflammatory responses. Proc Natl Acad Sci U S A 119(4):e2107742119 |
| abstractText | 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-kappaB and MAP kinase signaling pathways and thus attenuate induction of proinflammatory cytokines, particularly IL-1beta. 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. |
