Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis

Area of Science:

• Cellular Metabolism
• Immunology
• Molecular Biology

Background:

• In vitro studies link oxidative phosphorylation (OXPHOS) to anti-inflammatory macrophages and glycolysis to pro-inflammatory ones.
• The metabolic requirements of tissue macrophages in their native environments are not fully understood.

Purpose of the Study:

• To investigate the metabolic processes that differentiate tissue macrophages (TMFs) across various organs.
• To determine the role of OXPHOS in TMF function and homeostasis, especially in lipid metabolism and disease states.

Main Methods:

• Analysis of RNA-sequencing data from human and mouse tissues to identify key metabolic processes in TMFs.
• Genetic manipulation using Tfam deletion to impair OXPHOS in TMFs.
• In vivo studies to assess the impact of impaired OXPHOS on macrophage populations, cellular stress, and metabolic diseases like obesity.

Main Results:

• OXPHOS was identified as the most significant discriminating metabolic process among TMFs from different organs in homeostasis.
• Tfam deletion, impairing OXPHOS, reduced alveolar macrophages (AMs) due to impaired lipid handling, increased cellular stress, and cell-cycle arrest.
• In obesity, Tfam depletion selectively eliminated pro-inflammatory white adipose tissue macrophages (WAT-MFs), preventing insulin resistance and hepatosteatosis.

Conclusions:

• OXPHOS, not glycolysis, is the key metabolic pathway distinguishing TMF populations.
• OXPHOS is critical for maintaining TMFs involved in high lipid handling, including pro-inflammatory WAT-MFs.
• Targeting OXPHOS presents a potential therapeutic strategy for managing metabolic disorders associated with macrophage dysfunction.