Contribution of metabolic reprogramming to macrophage plasticity and function

Abstract

Macrophages display a spectrum of functional activation phenotypes depending on the composition of the microenvironment they reside in, including type of tissue/organ and character of injurious challenge they are exposed to. Our understanding of how macrophage plasticity is regulated by the local microenvironment is still limited. Here we review and discuss the recent literature regarding the contribution of cellular metabolic pathways to the ability of the macrophage to sense the microenvironment and to alter its function. We propose that distinct alterations in the microenvironment induce a spectrum of inducible and reversible metabolic programs that might form the basis of the inducible and reversible spectrum of functional macrophage activation/polarization phenotypes. We highlight that metabolic pathways in the bidirectional communication between macrophages and stromals cells are an important component of chronic inflammatory conditions. Recent work demonstrates that inflammatory macrophage activation is tightly associated with metabolic reprogramming to aerobic glycolysis, an altered TCA cycle, and reduced mitochondrial respiration. We review cytosolic and mitochondrial mechanisms that promote initiation and maintenance of macrophage activation as they relate to increased aerobic glycolysis and highlight potential pathways through which anti-inflammatory IL-10 could promote macrophage deactivation. Finally, we propose that in addition to their role in energy generation and regulation of apoptosis, mitochondria reprogram their metabolism to also participate in regulating macrophage activation and plasticity.

Keywords: Aerobic glycolysis; Arginase1; Fibroblast; IL-10; Inflammation; Krebs cycle; Mitochondria; Nitric oxide; Pulmonary hypertension.

Figure 1. Integration of glycolysis with TCA cycle and mitochondrial oxidative phosphorylation

Shown are the glycolytic pathway and the mitochondrial TCA cycle. Also show is the mitochondrial respiratory chain when operating in oxphos. Electron transport (yellow line) enables proton gradient, which is used to generate ATP by ATP synthase after oxygen has served as the terminal electron acceptor at complex 4. G6P: glose-6-phosphate; FBP: Fructose bisphosphatase; G3P: Glyceraldehyde 3-phosphate; PGLY: 3-phosphoglycerolphopsphate; Trnasort chin complexes (C-C4).

Figure 2. Metabolic adaptations in the inflammatory macrophage

Metabolic reprogramming of the inflammatory (LPS/IFNγ activated) macrophage involves increased expression of HIF1 and PKM2 protein, which increases glycolysis. Concomitant suppression of CARKL increases the pentose phosphate pathway (PPP), providing antioxidants reducing equivalents (NADPH). ATP generated by glycolysis is used to maintain energy demands in the face of concomitantly reduced mitochondrial respiration (reduced oxphos), which occurs secondary to inhibition of SDH (which is complex II, C2). Glycolysis derived ATP is also used to fuel “in reverse” operating ATP synthase in the mitochondria in order to maintain membrane potential and mitochondrial integrity. The inhibition of SDH promotes accumulation of succinate, which inhibits cytosolic prolylhydroxylases (PHDs) which usually mediate HIF1 degradation, thus increasing HIF1 stabilization and thus increased transcription of Il1b and glycolytic enzymes, and Arginase1. Succinate also inhibits complex I in the mitochondria which promotes ROS generation, which in turn enhances PHD inhibition and cytokine generation through stabilization of HIF1. In addition, expression of IDH is suppressed, resulting in citrate accumulation. To maintain anerplerosis of TCA cycle intermediates, inflammatory macrophages upregulate the argininosuccinate and citrulline-arginine cycle (orange), modify the malate aspartate shuttle (green) towards utilization of the argininiosuccinate cycle (red). This maintains fumarate anerplerosis and regenerates arginine for NO synthesis by iNOS. Furthermore, Arginine can be used for glutamate synthesis to replenish the TCA cycle in order to maintain succinate generation. Upregulation of the argininosuccinate and citrulline-arginine cycle also makes cells less sensitive to extracellular arginine limitation. NO also inhibits the respiratory chain further enhancing ROS production and succinate accumulation (not depicted). In the mitochondria, disruption of electron transport chain (inhibition of SDH that is Complex2, and production of NO) promotes reverse electron transport on complex 1 (yellow line), which increase ROS formation. Reduced proton gradient reduced membrane potential (not shown), which is prevented from breaking down completely by ATP synthase operating in reverse. ASS: Argininosuccinate synthase; ASL: Argininosuccinate lyase; a-KG: alpha-ketoglutarate; C1-C4: complexes of the mitochondrial respiratory electron transport chain 1–4. PHDs: prolyl hydroxylases; iNOS: inducible nitric oxide synthase; OXPHOS: oxidative phosphorylation; NO: nitric oxide; Glut1: glucose transporter1; HIF: hypoxia inducible factor; IDH: isocitrate dehydrogenase; SDH: succinate dehydrogenase; CARKL: carbohydrate kinase-like protein