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 andTh1 andTh2 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.