Mitochondrial metabolism regulates macrophage biology

Abstract

Mitochondria are critical for regulation of the activation, differentiation, and survival of macrophages and other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes to mitochondrial metabolism and physiology could underlie the corresponding state of macrophage activation. These changes include alterations of oxidative metabolism, mitochondrial membrane potential, and tricarboxylic acid (TCA) cycling, as well as the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) and transformation of the mitochondrial ultrastructure. Here, we provide an updated review of how changes in mitochondrial metabolism and various metabolites such as fumarate, succinate, and itaconate coordinate to guide macrophage activation to distinct cellular states, thus clarifying the vital link between mitochondria metabolism and immunity. We also discuss how in disease settings, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response. Therefore, mitochondria are a vital source of dynamic signals that regulate macrophage biology to fine-tune immune responses.

Keywords: macrophage activation; macrophage biology; mitochondrial dysfunction; mitochondrial metabolism; oxidative stress.

Figure 1

The effect of TCA intermediates on macrophage activation. Proinflammatory macrophages exhibit two breaks in the TCA cycle (at IDH and SDH), leading to the accumulation of citrate and succinate, and induction of the arginine-succinate shunt (AST) to support NO production. Itaconate, produced by the enzyme immune-responsive gene 1 (IRG1), exerts anti-inflammatory effects by inhibiting the activity of SDH and stimulating Nrf2 and activating transcription factor 3 (ATF3) induction. Fumarate, another TCA metabolite, is highly antimicrobial toward L. monocytogenes under acidic conditions by inhibiting the GAD (glutamic acid decarboxylase) system, which results in intracellular pH increase. It also has an inhibitory effect on aerobic glycolysis by suppressing GAPDH activity.

Figure 2

Mitochondrial metabolism modulates gene expression in inflammatory and IL-4-stimulated macrophages. In inflammatory macrophages activated by microbial signals, mitochondrial fission dampens ETC efficiency and enhances aerobic glycolysis. Elevated ΔΨm leads to accumulation of mtROS and induction of Il1b gene and voltage-regulated genes (VRGs), all contribute to macrophage function. In IL-4-stimulated macrophages, mitochondrial fusion stimulates interactions between ETC complexes that are conducive to OXPHOS and FAO. PGE2 modulates the expression of genes encoding the malate-aspartate shuttle (MAS), leading to the decrease of ΔΨm, which increases the activity of ETS variant 1 (ETV1) to promote some IL-4-inducible gene expression. Degradation or turnover of mitochondria via mitophagy is regulated by BNIP3L/NIX receptor and AMPK and mTOR pathway.

Figure 3

Mitochondrial stress and mtROS in the inflammatory response. Mitochondrial dysfunction including mtROS generation, reduced ATP synthesis and glutathione levels, and mtDNA release into the cytosol may all lead to mitochondrial stress. Cytoplasmic mtDNA can stimulate type I IFN responses via the cGAS-STING-IRF3 pathway and activate NLRP3 inflammasome and TLR9 pathway to increase proinflammatory cytokines production. mtROS production has been shown to cause DNA damage, unfolded protein response (UPR), and inflammatory responses through HIF-1α and MAPK/NF-κB pathways in LPS-stimulated macrophages.