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.

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“…Apart from dendritic cells, classical/proinflammatory/M1 macrophages also participate in the induction of a polarized Th1 response and have been associated with resistance to intracellular pathogens (22,(27)(28)(29)(30)(31). Of interest, such a polarization of T cells by proinflammatory (M1) macrophages was associated with induction of protection in several vaccine studies, including studies of recombinant Mycobacterium bovis BCG, attenuated West Nile virus (WNV), and live attenuated measles virus (32)(33)(34).…”

The Ron Receptor Tyrosine Kinase Regulates Macrophage Heterogeneity and Plays a Protective Role in Diet-Induced Obesity, Atherosclerosis, and Hepatosteatosis

“…These cells tend to be broadly characterized as alternatively activated macrophages (M2) or reparative macrophages, whereas in response to infection or tissue damage, inflammatory macrophages (M1) predominate (6,7). These two phenotypes are typified by the expression of inducible NO synthase (iNOS) and arginase 1 (Arg1), which share a common substrate, L-arginine (8)(9)(10). Arg1 converts L-arginine to polyamides and prolines promoting proliferation and matrix synthesis, whereas iNOS converts L-arginine to NO, which is cytotoxic (10,11).…”

“…These two phenotypes are typified by the expression of inducible NO synthase (iNOS) and arginase 1 (Arg1), which share a common substrate, L-arginine (8)(9)(10). Arg1 converts L-arginine to polyamides and prolines promoting proliferation and matrix synthesis, whereas iNOS converts L-arginine to NO, which is cytotoxic (10,11). However, the origin and/or plasticity of these cells remain loosely defined.…”

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