Metabolic reprogramming of macrophages and its involvement in inflammatory diseases

Abstract

Macrophages are critical effector cells of the innate immune system. The presence of microbes or the stimulation by inflammatory factors triggers the metabolic reprogramming of macrophages or macrophage polarization into two phenotypes: the classically activated macrophages (M1) displaying a pro-inflammatory phenotype and the alternatively activated macrophages (M2) having anti-inflammatory functions. The imbalance between the two phenotypes has been linked with various pathological states, such as fibrosis, hepatitis, colitis, and tumor progression. An avenue of potential therapeutic strategies based on macrophage polarization has emerged. Therefore, it is essential to understand the mechanisms of macrophage polarization. In this review, we focus on the macrophage polarization process and discuss the stimuli-dependent conversion into M1 and M2 phenotypes. We also present the metabolic patterns supporting their specific functions. The factors and signaling cascades involved in intra-class switching are also detailed. Finally, the role of macrophage polarization in disease progression is discussed.

Keywords: inflammation; macrophage; metabolic reprogramming; polarization; tissue repair.

Table 1. Classification of M1/M2 macrophages and signaling pathways involved in their polarization

Figure 1. Metabolic reprogramming into M1 phenotype. Stimulation with LPS, INF-γ, or TNFα of macrophages favors a reprogramming toward the pro-inflammatory phenotype. One of the very first events is the TCA cycle halt resulting in the accumulation of citrate and succinate. The dysfunction of the TCA cycle activates a metabolic process known as the “Warburg effect.” The accumulation of succinate inhibits the succinate dehydrogenase (SDH) increasing the level of HIF-1α, a signaling molecule characteristic of the M1 phenotype. Inducible NO synthase, adenosine 5′-monophosphate-activated protein kinase (AMPK) pathway, ROS, and other pathways are also involved in this metabolic system. See text for details.

Figure 2. Metabolic reprogramming in M2 phenotype. The stimulation with IL-4, IL-13, IL-10, TGF-β, or GC provokes the metabolic reprogramming of macrophages into the anti-inflammatory phenotype (M2). In M2 macrophages, arginine is metabolized to collagen and ornithine by arginase-1 (Arg-1) in the urea cycle. The M2 phenotype relies on FAO and OXPHOS to generate energy. FAO supplies energy to generate acetyl-CoA which enters the TCA cycle and OXPHOS producing higher amounts of ATP than glycolysis. Besides, the anti-inflammatory macrophages can yield pro-resolving molecules, such as IL-10 and TGF-β, thus promoting tissue repair and remodeling. See text for details.

Figure 3. Signaling pathways triggering pro-inflammatory (M1) reprogramming. Stimulation by IL-6, IL-1β, and TNFα triggers IKKβ to phosphorylate and degrade IκB, resulting in the release of NF-κB (p50-p65). NF-κB (p50-p65) enters the nucleus and binds to its target DNA response elements, activating pro-inflammatory genes. In addition, JNK is phosphorylated and activates c-Jun, subsequently activating pro-inflammatory target genes, which are partly common with NF-κB. See text for details.

Figure 4. Signaling pathways triggering anti-inflammatory (M2) reprogramming. IL-4 and IL-13 induce the tyrosine phosphorylation of STAT6, leading to the formation of phosphorylated STAT6 dimers. These enter the nucleus and bind to the target DNA, enhancing the expression of anti-inflammatory genes. In addition, the phosphorylated STAT6 dimers use PGC1β as a coactivator to promote the anti-inflammatory metabolic reprogramming of macrophages by PPARγ and PPARδ. See text for details.