Macrophage cells are composed of various organelles, such as nucleus, cytoplasm, plasma membrane, lysosomes, mitochondria, Golgi complex, endoplasmic reticulum, etc. They have different shapes and phenotypes depending on their location and activation state. Macrophages have a complex metabolism, involving glycolysis, oxidative phosphorylation, fatty acid synthesis and oxidation, amino acid metabolism, etc. They can adapt their metabolism to different environmental stimuli and functional demands.

Creative Biolabs summarizes the current knowledge on the composition and metabolism of macrophages, and discusses how they affect their functions in immunity, inflammation, tissue homeostasis, and repair.

Macrophage Composition

The composition of macrophages is not static, but dynamic and adaptable to the changing conditions of the tissue microenvironment. Macrophages are composed of various molecular and cellular components that enable them to perform their diverse functions in immunity, inflammation, tissue homeostasis, and repair. Some of the key components of macrophages are:

• Surface receptors: Macrophages express a variety of surface receptors that allow them to sense and respond to different signals from the environment. These receptors include pattern recognition receptors (PRRs), cytokine receptors, and scavenger receptors.
• Cytoskeleton: Macrophages have a dynamic cytoskeleton that consists of actin filaments, microtubules, and intermediate filaments. The cytoskeleton is involved in various processes, such as cell shape, motility, macrophage phagocytosis, cytokinesis, and intracellular trafficking.
• Organelles: Macrophages have several organelles that are essential for their functions. These include the nucleus, the endoplasmic reticulum (ER) and the Golgi apparatus, the lysosomes, the mitochondria, the peroxisomes, and the autophagosomes.
• Secretory products: Macrophages secrete a variety of molecules that modulate the immune response and the tissue microenvironment. These include cytokines, chemokines, growth factors, enzymes, and antimicrobial peptides.

Macrophage Metabolism

• Metabolic Pathways of Macrophages
  Macrophage metabolism is the process by which macrophages acquire, utilize, and store energy and nutrients to support their functions. Macrophage metabolism involves several metabolic pathways, such as glycolysis, oxidative phosphorylation, fatty acid synthesis, and fatty acid oxidation. These pathways are interconnected and regulated by various enzymes, transcription factors, and signaling molecules. Most importantly, the metabolic pathways of m1 and m2 macrophages are not mutually exclusive, but complementary and coordinated to meet the diverse and dynamic demands.

  Fig.1 Overview of macrophage metabolic pathways.¹

  • Glycolysis: Glycolysis is the breakdown of glucose into pyruvate, which generates two molecules of ATP and two molecules of NADH.
    • Glycolysis is a fast and efficient way of producing energy for macrophages, especially under hypoxic or inflammatory conditions.
    • Glycolysis is enhanced in M1 macrophages, which have high demand for ATP and biosynthetic precursors for cytokine production and nitric oxide synthesis.
  • Oxidative phosphorylation: Oxidative phosphorylation is the oxidation of NADH and FADH2 by the electron transport chain in the mitochondria, which generates a proton gradient that drives the synthesis of ATP-by-ATP synthase.
    • Oxidative phosphorylation is a slow but efficient way of producing energy for macrophages, especially under normoxic or anti-inflammatory conditions.
    • Oxidative phosphorylation is enhanced in M2 macrophages, which have low demand for ATP and biosynthetic precursors, but high demand for oxygen and carbon dioxide for fatty acid oxidation and arginine metabolism.
  • Fatty acid synthesis: Fatty acid synthesis is the synthesis of fatty acids from acetyl-CoA and malonyl-CoA by fatty acid synthase (FAS) in the cytosol.
    • Fatty acids are important components of cell membranes, lipid droplets, and signaling molecules for macrophages.
    • Fatty acid synthesis is enhanced in M1 macrophages, which have high demand for membrane expansion and lipid mediators, such as prostaglandins and leukotrienes.
  • Fatty acid oxidation: Fatty acid oxidation is the breakdown of fatty acids into acetyl-CoA by beta-oxidation in the mitochondria or peroxisomes.
    • Fatty acid oxidation is a major source of energy and ketone bodies for macrophages.
    • Fatty acid oxidation is enhanced in M2 macrophages, which have high demand for oxygen and carbon dioxide for arginine metabolism and urea cycle.
• Regulation of Macrophage Metabolism
  Macrophage metabolism is regulated by external stimuli, such as cytokines, pathogens, hypoxia, and nutrient availability, that modulate the activity and expression of various enzymes, transcription factors, and signaling molecules involved in the metabolic pathways. Some examples of how external stimuli regulate macrophage metabolism are:
  • Cytokines: Cytokines can have different effects on macrophage metabolism depending on their type and concentration.
  • Pathogens: Pathogens can trigger macrophage metabolism by binding to PRRs, such as TLRs and CLRs, that activate various signaling pathways, such as NF-κB and MAPK.
  • Hypoxia: Hypoxia can affect macrophage metabolism by stabilizing HIF-1α, a transcription factor that senses oxygen levels and regulates the expression of genes involved in glycolysis, angiogenesis, and inflammation.
  • Nutrient availability: Nutrient availability can influence macrophage metabolism by altering the substrate availability and the energy status of the cell.
• Effects of Macrophage Metabolism
  Macrophage metabolism affects the functions in immunity, inflammation, tissue homeostasis, and repair by modulating their production and consumption of various molecules that mediate these processes. Some examples of how macrophage metabolism affects their functions are:

  Fig.2 Functions of adipose tissue macrophages in lipid metabolism.²

  • Immunity: Macrophage metabolism influences their ability to kill or inhibit the growth of pathogens, such as bacteria, viruses, fungi, and parasites.
  • Inflammation: Macrophage metabolism influences the production and secretion of various cytokines, chemokines, and lipid mediators that regulate inflammation and immunity.
  • Tissue homeostasis: Macrophage metabolism influences the maintenance and regulation of tissue homeostasis by modulating their clearance of apoptotic cells, debris, and toxins.
  • Tissue repair: Macrophage metabolism influences the promotion and facilitation of tissue repair by modulating the production and secretion of various growth factors, enzymes, and extracellular matrix components.

In conclusion, macrophages have many organelles that help them perform their functions, such as lysosomes that digest the engulfed material, mitochondria that provide energy, and endoplasmic reticulum that synthesizes proteins and lipids. Macrophages can change their shape and behavior according to the signals they receive from the environment. They can also switch their metabolism to use different sources of fuel and produce different molecules that affect the immune response.

Macrophages are versatile and adaptable cells that play a key role in immunity. Creative Biolabs provides a variety of macrophage related products and services to help researchers.

References

1. Viola, Antonella, et al. "The metabolic signature of macrophage responses." Frontiers in Immunology 10 (2019): 1462.
2. Wculek, Stefanie K., et al. "Metabolism of tissue macrophages in homeostasis and pathology." Cellular & molecular immunology 19.3 (2022): 384-408.