Myeloid cell TBK1 restricts inflammatory responses.

Area of Science:

• Immunology
• Molecular Biology
• Metabolic Diseases

Background:

• Proinflammatory cytokine production by innate immune cells is central to inflammatory diseases.
• The precise molecular mechanisms governing these inflammatory responses remain incompletely understood.

Purpose of the Study:

• To investigate the role of TANK-binding kinase 1 (TBK1) in regulating macrophage function and inflammatory responses.
• To determine the impact of TBK1 deficiency in myeloid cells on metabolic health and inflammation.

Main Methods:

• Generation of myeloid cell-conditional Tbk1 knockout (MKO) mice.
• Assessment of metabolic parameters, adipose tissue inflammation, and hepatic steatohepatitis in MKO mice under normal and high-fat diet conditions.
• Evaluation of inflammation in experimental colitis models with myeloid-specific TBK1 ablation.
• Mechanistic studies involving NF-κB and MAP kinase signaling pathways and IL-1 receptor 1 (IL-1R1) ablation.

Main Results:

• Myeloid cell-conditional Tbk1 knockout mice exhibited spontaneous adipose hypertrophy, metabolic disorders, and increased M1 macrophage infiltration with elevated proinflammatory cytokine expression.
• Tbk1-MKO mice on a high-fat diet showed exacerbated hepatic inflammation and insulin resistance, mimicking nonalcoholic steatohepatitis.
• TBK1 deficiency in myeloid cells worsened inflammation in experimental colitis.
• TBK1 was found to suppress NF-κB and MAP kinase signaling in macrophages, thereby reducing proinflammatory cytokine production, particularly IL-1β.
• Ablation of IL-1R1 abolished the inflammatory phenotype in Tbk1-MKO mice.

Conclusions:

• TBK1 is a critical negative regulator of proinflammatory macrophage function.
• TBK1 acts as a pivotal anti-inflammatory mediator, protecting against tissue inflammation in various disease models by suppressing key inflammatory signaling pathways.
• Targeting TBK1 or its downstream effectors like IL-1R1 may offer therapeutic strategies for inflammatory and metabolic diseases.