Mitochondrial Dysfunction Prevents Repolarization of Inflammatory Macrophages

Abstract

Macrophages are innate immune cells that adopt diverse activation states in response to their microenvironment. Editing macrophage activation to dampen inflammatory diseases by promoting the repolarization of inflammatory (M1) macrophages to anti-inflammatory (M2) macrophages is of high interest. Here, we find that mouse and human M1 macrophages fail to convert into M2 cells upon IL-4 exposure in vitro and in vivo. In sharp contrast, M2 macrophages are more plastic and readily repolarized into an inflammatory M1 state. We identify M1-associated inhibition of mitochondrial oxidative phosphorylation as the factor responsible for preventing M1→M2 repolarization. Inhibiting nitric oxide production, a key effector molecule in M1 cells, dampens the decline in mitochondrial function to improve metabolic and phenotypic reprogramming to M2 macrophages. Thus, inflammatory macrophage activation blunts oxidative phosphorylation, thereby preventing repolarization. Therapeutically restoring mitochondrial function might be useful to improve the reprogramming of inflammatory macrophages into anti-inflammatory cells to control disease.

Macrophage functions in lean and obese adipose tissue

“…M1 macrophages fail to repolarize into M2 macrophages with IL-4 exposure, whereas M2 macrophages can be repolarized into M1 98 . M1 macrophages rely on glycolysis whereas M2 macrophages rely on oxidative phosphorylation.…”

“…NO released by macrophages induces mitochondrial dysfunction by suppressing PGC-1α which can be blocked by rosiglitazone. Pretreatment of macrophages with an iNOS inhibitor reduces mitochondrial dysfunction induced by LPS and IFN-γ and shifts macrophages towards M2 polarization 98 . Hence, oxidative stress induces M1 macrophage polarization.…”

Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity

“…NO actually causes nitrosylation of the iron–sulfur-containing ETC complexes and consequently inhibits mitochondrial respiration and OXPHOS (38, 39). Recent research by Van den Bossche and colleagues demonstrated that disturbed mitochondrial OXPHOS, caused by IFNγ/LPS-induced NO production, can prevent M1 to M2 polarization after IL-4 stimulation (40). Furthermore, PPP-produced NADPH can be used as a cofactor for NADPH oxidase, which is involved in the generation of ROS (41).…”

The effect of oxidized phospholipids on phenotypic polarization and function of macrophages

“…Recently, multiple studies identified the importance of cellular metabolism in the determination of macrophage pro-[96] or anti-inflammatory[97] function. Further investigation revealed that the mitochondrial dysfunction caused by pro-inflammatory stimuli prevented macrophages from assuming an anti-inflammatory polarization state[98]. …”