Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages

Abstract

Macrophages play a major role in the immune system, both as antimicrobial effector cells and as immunoregulatory cells, which induce, suppress or modulate adaptive immune responses. These key aspects of macrophage biology are fundamentally driven by the phenotype of macrophage arginine metabolism that is prevalent in an evolving or ongoing immune response. M1 macrophages express the enzyme nitric oxide synthase, which metabolizes arginine to nitric oxide (NO) and citrulline. NO can be metabolized to further downstream reactive nitrogen species, while citrulline might be reused for efficient NO synthesis via the citrulline-NO cycle. M2 macrophages are characterized by expression of the enzyme arginase, which hydrolyzes arginine to ornithine and urea. The arginase pathway limits arginine availability for NO synthesis and ornithine itself can further feed into the important downstream pathways of polyamine and proline syntheses, which are important for cellular proliferation and tissue repair. M1 versus M2 polarization leads to opposing outcomes of inflammatory reactions, but depending on the context, M1 and M2 macrophages can be both pro- and anti-inflammatory. Notably, M1/M2 macrophage polarization can be driven by microbial infection or innate danger signals without any influence of adaptive immune cells, secondarily driving the T helper (Th)1/Th2 polarization of the evolving adaptive immune response. Since both arginine metabolic pathways cross-inhibit each other on the level of the respective arginine break-down products and Th1 and Th2 lymphocytes can drive or amplify macrophage M1/M2 dichotomy via cytokine activation, this forms the basis of a self-sustaining M1/M2 polarization of the whole immune response. Understanding the arginine metabolism of M1/M2 macrophage phenotypes is therefore central to find new possibilities to manipulate immune responses in infection, autoimmune diseases, chronic inflammatory conditions, and cancer.

Keywords: M1 and M2; amino acid transporter; arginase; arginine; immunoregulation; macrophage; nitric oxide synthase.

Figure 1

Important pathways of mammalian arginine metabolism. M1 and M2 macrophages are characterized by the metabolism of arginine via NOS or arginase with important functional consequences. This dichotomy is put into the context of other important pathways that can lead to the synthesis or degradation of arginine in mammalian cells. For sake of clarity, the diagram focuses on relevant enzymes (gray-shaded boxes), metabolites (red boxes), and the position of NOS and arginase within the network is highlighted. Various intermediate steps, by-products, or substrates are omitted and the reader is referred to more extensive chemical reviews (see text). ADC, arginine decarboxylase; AGAT, arginine:glycine amidinotransferase; ASL, argininosuccinate lyase, ASS, argininosuccinate synthase; CP, carbamoyl phosphate; CPS, CP synthase; NOS, nitric oxide synthase; OAT, ornithine aminotransferase; ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase; P5C, pyrroline-5-carboxylate; P5CDH, P5C dehydrogenase; P5CR, P5C reductase; P5CS, P5C synthase; PRODH, proline dehydrogenase; SRS, spermidine synthase; SMS, spermine synthase.

Figure 2

Arginine metabolism via NOS or arginase is at the center of the M1/M2 polarization of macrophages. M1 and M2 macrophages are characterized by the metabolism of arginine via NOS or arginase with important functional consequences. Abbreviations: see Figure 1.