Macrophages, Meta-Inflammation, and Immuno-Metabolism

Figure 2

Coregulation of immune phenotype and metabolic mode in macrophages. Recruited macrophages display striking phenotype plasticity in the course of acute, spontaneously resolving inflammation. Upon exudation into edematous, hypoxic tissue, macrophages initially acquire the proinflammatory and microbicidal M1 phenotype and depend on anaerobic glycolysis for ATP. Pathogen-associated molecular patterns, Th1-type cytokines (not shown), and hypoxia-sensitive transcription factors (HIF-1 and Pur, see text for details) cooperate to induce the expression both of M1 mediators (e.g., cytokines, iNOS, CD11b/CD18) and of the proteins/enzymes that perform anaerobic glycolysis. The insulin-independent glucose transporter (GLUT 1) facilitates glucose uptake; pyruvate kinase catalyzes pyruvate synthesis, lactate dehydrogenase produces lactate from pyruvate and generates NAD⁺ (required for further glycolysis). PDH-kinase inhibits pyruvate dehydrogenase, thereby diverting pyruvate away from the Krebs cycle, and towards lactate. With the clearance of microbes and ablation of edema, specialized proresolution mediators (SPM), Th2-type cytokines, and the uptake of apoptotic neutrophils (early efferocytosis) produce a phenotype switch to the M2 macrophage. IL-4 and IL-13 activate STAT6 transcriptive activity, inducing not only M2 signatures (e.g., nonopsonic endocytic receptors) but also two PPAR isoforms and 12/15-LO. The latter synthesizes SPMs—which promote further nonphlogistic recruitment and efferocytosis by macrophages—and intermediate metabolites (15-HETE and 17S-HDHA) that are necessary for PPAR activation. Lipids from engulfed neutrophils also provide PPARδ ligands. The PPARs in turn orchestrate mitochondrial biogenesis and the metabolic shift to aerobic metabolism of glucose and particularly fatty acids. PPARδ also reinforces efferocytosis by inducing receptors for apoptotic cells. Upregulated metabolic proteins/enzymes include fatty acid translocator CD36, enzymes that catalyze β-oxidation of fatty acids (e.g., LCAD-Long Chain Acyl CoA Dehydrogenase), Krebs cycle enzymes (e.g., citrate synthase), pyruvate dehydrogenase, which enables glycolysis-derived pyruvate to enter the Krebs cycle, and constituents of the Electron Transport Chain that perform oxidative phosphorylation. Inhibition of these metabolic pathways hampers M2 function [1]. Handling of fatty acids by adipose tissue M2 constitutes a unique metabolic function in that cells up-take, catabolize or esterify (not shown) fatty acids released by adipocytes, thereby constraining the level of these potentially harmful molecules within a normal range. On-going efferocytosis “satiates” the macrophage that ceases cell engulfment and promotes the resolution of inflammation, that is, phenotype switching to Mres (CD11b^low). The metabolic mode and signaling cascades that regulate immune and metabolic functions of Mres remain to be elucidated.