Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections

Abstract

Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.

Keywords: SARS – CoV – 2; immunometabolism; infections; macrophage; therapeutics.

Figure 1

Overview of the main metabolic pathways used by macrophages. There are 5 major pathways used by macrophages to provide energy in cells including glycolysis, TCA (Tricarboxylic acid) cycle, PPP (Pentose phosphate pathway), FAS (Fatty acid synthesis) and FAO (Fatty acid oxidation) and amino acid (Aa) metabolism. These pathways are highly interconnected and are tightly regulated in immune cells, including macrophages. ACLY, ATP citrate lyase; ACO2, Aconitase 2; ATP, Adenosine triphosphate; CPT1, Carnitine palmitoyltransferase 1; CS, Citrate synthase; ENO, Enolase; FH, Fumarase; GAPDH, Glyceraldehyde 3-phosphate dehydrogenase; GLUT1, Glucose transporter 1; HK, Hexokinase; GS, Glutamine synthetase; IDH, Isocitrate dehydrogenase; IDO, Indoleamine 2,3-dioxygenase; LDHA, Lactate dehydrogenase; MCT1, Monocarboxylate transporter 1; MDH, Malate dehydrogenase; NO, Nitric oxide; iNOS, inducible NO synthase; OAA, Oxaloacetate; OGDH, α-ketoglutarate dehydrogenase; OXPHOS, Oxidative phosphorylation; P, Phosphate; PDH, Pyruvate dehydrogenase; PFK1,Phosphofructokinase 1; PGK1, Phosphoglycerate kinase 1; PGI, Phosphoglucoisomerase; PGM, Phosphoglycerate mutase; PKM, Pyruvate kinase muscle isotype; PP, bisphosphate; SAM, S-Adenosyl methionine; SCS, Succinyl coenzyme A synthetase; SDH, Succinate dehydrogenase; SLC, Solute carrier; TDO, Tryptophan 2,3-dioxygenase; TPI1, Triosephosphate isomerase 1.

Figure 2

Phenotypic characteristics of pro- versus anti-inflammatory macrophages. Pro-inflammatory stimuli (like TLR ligands or pro-inflammatory cytokines) will generate a pro-inflammatory response in macrophages, notably characterized by the production of pro-inflammatory cytokines, the expression of co-stimulatory molecules and a Th1 response. On the other hand, anti-inflammatory stimuli (like IL4, IL13 or IL10) will promote a pro-repair phenotype in macrophages notably caracterized by the production of anti-inflammatory and pro-resolutive factors and the generation of a Th2 response. In the context of infection, the generation of pro-inflammatory macrophages will promote their killing activity but microbes will try to promote the generation of anti-inflammatory phenotype to escape these responses. Anti-inflammatory macrophages, while promoting infections in general, will have a strong anti-helminth effect. Metabolically, the pro-inflammatory macrophages use glycolysis and PPP to produce energy and have a broken TCA cycle. Instead, anti-inflammatory macrophages use the FAO and OXPHOS to provide cellular energy. FAO, Fatty acid oxidation; IFN, Interferon; IL, Interleukin; LPS, Lipopolysaccharide; OXPHOS, Oxidative phosphorylation; NO, Nitric oxide; PPP, Pentose phosphate pathway; TCA, Tricarboxylic acid; Th, T helper; TLR, Toll like receptor; TNFα, Tumor necrosis factor alpha.