Reprogramming mitochondrial metabolism in macrophages as an anti‐inflammatory signal

2015/12/08 by Evanna L. Mills, Luke A. O'Neill, Luke O'neill · 457 citations
Immunology and Microbiology · Medicine · #Autophagy in Disease and Therapy #Biochemistry #Biology #Cell biology #Citric acid cycle #Glycolysis #Immune Cell Function and Interaction #Immune cells in cancer #In vitro #Macrophage #Metabolism #Mitochondrion #Oxidative phosphorylation #Reactive oxygen species

paper · pdf · doi:10.1002/eji.201445427

published in European Journal of Immunology 46(1), 13-21 (Wiley)

openalex publication_date 2015/12/08 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/26

Abstract

Mitochondria are master regulators of metabolism. Mitochondria generate ATP by oxidative phosphorylation using pyruvate (derived from glucose and glycolysis) and fatty acids (FAs), both of which are oxidized in the Krebs cycle, as fuel sources. Mitochondria are also an important source of reactive oxygen species (ROS), creating oxidative stress in various contexts, including in the response to bacterial infection. Recently, complex changes in mitochondrial metabolism have been characterized in mouse macrophages in response to varying stimuli in vitro. In LPS and IFN-γ-activated macrophages (M1 macrophages), there is decreased respiration and a broken Krebs cycle, leading to accumulation of succinate and citrate, which act as signals to alter immune function. In IL-4-activated macrophages (M2 macrophages), the Krebs cycle and oxidative phosphorylation are intact and fatty acid oxidation (FAO) is also utilized. These metabolic alterations in response to the nature of the stimulus are proving to be determinants of the effector functions of M1 and M2 macrophages. Furthermore, reprogramming of macrophages from M1 to M2 can be achieved by targeting metabolic events. Here, we describe the role that metabolism plays in macrophage function in infection and immunity, and propose that reprogramming with metabolic inhibitors might be a novel therapeutic approach for the treatment of inflammatory diseases.

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