The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome

Abstract

Lung macrophages constitute the first line of defense against airborne particles and microbes and are key to maintaining pulmonary immune homeostasis. There is increasing evidence suggesting that macrophages also participate in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), including the modulation of inflammatory responses and the repair of damaged lung tissues. The diversity of their functions may be attributed to their polarized states. Classically activated or inflammatory (M1) macrophages and alternatively activated or anti-inflammatory (M2) macrophages are the two main polarized macrophage phenotypes. The precise regulatory mechanism of macrophage polarization is a complex process that is not completely understood. A growing body of literature on immunometabolism has demonstrated the essential role of immunometabolism and its metabolic intermediates in macrophage polarization. In this review, we summarize macrophage polarization phenotypes, the role of immunometabolism, and its metabolic intermediates in macrophage polarization and ALI/ARDS, which may represent a new target and therapeutic direction.

Keywords: acute lung injury; acute respiratory distress syndrome; immunometabolism; macrophage polarization; metabolic reprogramming; polarization regulation.

Figure 1

Regulatory mechanisms and functional characteristics of macrophage polarization. Non-polarized M0 macrophages can be polarized into M1 macrophages stimulated by LPS, IFN-γ, and GM-CSF, which are associated with increased glycolysis, PPP, and FAS. In addition, M0 macrophages can be polarized into M2 macrophages in the presence of IL-4, IL-13, IL-10, and M-CSF, which is related to increased OXPHOS, FAO, and glutamine metabolism. Furthermore, these polarized macrophages exhibit plasticity, as they can depolarize to M0 macrophages or exhibit the opposite phenotype through repolarization, which depends on the specific microenvironment. M1 macrophages produce pro-inflammatory cytokines such as IL-1β, iNOS, TNF-α, IL-1, IL-6, IL-12, IL-23, CCL8, CXCL1-3, CXCL-5, CXCL8-10, MCP-1, MIP-2, ROS, and COX-2, leading to pro-inflammatory responses, chemotaxis, pathogenic microorganism elimination, and antitumoral activities. M2 macrophages can be further divided into four subsets, M2a, M2b, M2c, and M2d, according to the different activating stimuli received. M2 macrophages secrete anti-inflammatory cytokines such as IL-8, IL-10, IL-13, CCL1, CCL2, CCL3, CCL4, CCL13, CCL14, CCL17, CCL18, CCL22, CCL23, CCL24, and CCL26 to exert anti-inflammatory effects, promote tissue remodeling, facilitate tumor development, and remove parasites.

Figure 2

The metabolic pathways of M1 and M2 macrophages. M1 macrophages are associated with increased glycolysis, PPP, and FAS. The disturbed TCA cycle results in the accumulation of citrate and succinate. The accumulated citrate in the mitochondria of M1 macrophages is exported into the cytoplasm via the CIC and converted into acetyl-coenzyme A by ACLY. The downstream metabolic intermediate, acetyl-CoA, is necessary for TNF-α or IFN-γ to induce pro-inflammatory cytokines, such as NO and prostaglandin production. The malonylation response relies on citrate-derived metabolite malonyl-CoA production, which is an essential pro-inflammatory signal that promotes TNF translation and secretion by regulating glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Succinate is a critical regulator of the pro-inflammatory response and regulates the expression of IL-1β via the the stabilization of hypoxia-inducible factor 1-alpha (HIF-1α)., thereby promoting LPS-induced expression of IL-1β. SDH mediates succinate oxidation and reverses electron transport, which together drive mitochondrial ROS production and induce a pro-inflammatory gene expression profile. Extracellular succinate binds to SUCNR1 and increases IL-1β production, which in turn increases SUCNR1 levels, fueling this cycle of cytokine production and perpetuating inflammation. M2 macrophages rely more heavily on OXPHOS, glutamine metabolism, and FAO than M1 macrophages. The enhancement of OXPHOS in M2 macrophages results in the continued production of ATP, leading to the upregulation of genes associated with tissue repair. The downregulated enzyme carbohydrate kinase-like protein (CARKL) causes glycolysis to feed the PPP, thereby generating nucleotides, amino acids, and NADPH, leading to an increase in ROS. αKG produced by glutamine hydrolysis promoted M2 activation through Jmjd3-dependent metabolic and epigenetic reprogramming, and a high αKG/succinate ratio further promoted the anti-inflammatory phenotype in M2 macrophages, whereas a low ratio enhances the pro-inflammatory phenotype in M1 macrophages. Elevated metabolites and processes are highlighted in red, and suppressed processes are highlighted in green.