Molecular Mechanisms Modulating the Phenotype of Macrophages and Microglia

Abstract

Macrophages and microglia play crucial roles during central nervous system development, homeostasis and acute events such as infection or injury. The diverse functions of tissue macrophages and microglia are mirrored by equally diverse phenotypes. A model of inflammatory/M1 versus a resolution phase/M2 macrophages has been widely used. However, the complexity of macrophage function can only be achieved by the existence of varied, plastic and tridimensional macrophage phenotypes. Understanding how tissue macrophages integrate environmental signals via molecular programs to define pathogen/injury inflammatory responses provides an opportunity to better understand the multilayered nature of macrophages, as well as target and modulate cellular programs to control excessive inflammation. This is particularly important in MS and other neuroinflammatory diseases, where chronic inflammatory macrophage and microglial responses may contribute to pathology. Here, we perform a comprehensive review of our current understanding of how molecular pathways modulate tissue macrophage phenotype, covering both classic pathways and the emerging role of microRNAs, receptor-tyrosine kinases and metabolism in macrophage phenotype. In addition, we discuss pathway parallels in microglia, novel markers helpful in the identification of peripheral macrophages versus microglia and markers linked to their phenotype.

Keywords: central nervous system; inflammation; macrophages; metabolism; microRNA; microglia; molecular.

Figure 1

Key stimuli and molecular pathways in inflammatory vs. resolution phenotype in mononuclear phagocytes. Inflammatory and resolution macrophage phenotype results as external stimuli are integrated via signaling pathways to drive phenotype-supporting transcriptional programs and cellular metabolism. Red and blue color indicates pathways, stimuli, transcription factors and metabolic processes associated with inflammatory or resolution phenotype, respectively. Inflammatory phenotype is induced or promoted by pathogens, injured cells and in vitro stimuli. In contrast, resolution spectrum phenotypes are induced or promoted by parasites, fungi, apoptotic cells, immune complexes and other cytokine/growth factor stimuli. Pathogen or injury signals sensed via pathogen-recognition receptors (PRR) such as Toll-like receptors (TLR) result in Janus activated kinase (Jak)2 and nuclear factor kappa B (NF-κB) activation. Signals received via Notch receptors, cytokine receptor (CtkR), chemokine receptor (CCR), and Fc receptor (FcR) stimulation are also integrated, defining gene expression and downstream metabolic reprogramming. Interferon regulatory factors (IRFs) 5 and 8 promote inflammatory gene expression while IRF 4 promotes resolution phenotype genes. Gene expression promotes changes in nutrient uptake and metabolic pathways that support inflammatory or resolution macrophage phenotype. LPS, lipopolysaccharide; IFN-γ: interferon-γ; GM-CSF, granulocyte monocyte colony stimulation factor; IC, immune complexes; TGF-β, transforming growth factor-β; IL, interleukin; IL-1R, interleukin 1 receptor; M-CSF, monocyte colony stimulation factor; PI3K, phosphoinositide 3 kinase; AKT, serine threonine kinase; mTOR, mammalian target of rapamycin; PTEN, phosphatase and tensin homolog; TSC, tuberous sclerosis complex; c-MYC, PPAR, peroxisome proliferator activated receptor; ADAM, A disintegrin and metalloproteinase; RBP-J, recombination signal binding protein for immunoglobulin kappa J region; MAML, mastermind-like; Rictor, rapamycin-insensitive companion of mTOR; TCA, tricarboxylic acid/Krebs cycle.

Figure 2

Cellular metabolic pathways driving mononuclear phagocyte inflammatory vs. resolution phenotype. Glucose is essential for both inflammatory and resolution macrophage phenotypes. In inflammatory macrophages, glucose is largely processed to yield lactate via aerobic glycolysis. Another major pathway in M1 spectrum macrophages is conversion to ribose-5P via the pentose phosphate pathway (PPP) for synthesis of nucleotides and NADPH, which supports nitric oxide (NO), reactive oxygen species (ROS), and IL-1β production. In resolution macrophages, the major fate of glucose is the TCA/Krebs cycle via pyruvate dehydrogenase (PDH)-catalyzed conversion of pyruvate to AcetylCoA (AcCoA). The TCA cycle in resolution macrophages is also fed by fatty acids (FA) via the ATP-citrate lyase (Acly) enzyme and promotes forward electron transport chain (ETC), from C1 to CIV, for ATP generation. In contrast, while some glucose enters the mitochondria in inflammatory macrophages, where it is converted to citrate, the TCA cycle is broken, with stops at the isocitrate dehydrogenase (IDH) and succinate dehydrogenase (SHD) steps. Citrate accumulation results in itaconate production, which inhibits SDH, and also promotes prostaglandin (PG), lipid and FA synthesis. In inflammatory macrophages, these blocks promote reverse electron transport chain (RET) from CII to CI. GLUT1, glucose transporter 1/SLC2A1; HK2, hexokinase 2; Glucose-6P, glucose-6-phosphate; LDH, lactose dehydrogenase; PHK1, pyruvate dehydrogenase kinase 1; AcCoa, acetyl coenzyme A; TCA, tricarboxylic acid/Krebs cycle; a-KG, a-ketoglutarate; CI-IV, ETC complexes I–IV, SDH, succinate dehydrogenase; OAA, oxaloacetate; e^-, electrons; RET, reverse electron transport chain; iNOS, inducible nitric oxide synthase; HIF-1α, hypoxia inducible factor-1α. Enzymes are indicated by bold font.