Macrophages are involved in inflammation from induction to resolution. Polarization of macrophages along the M1 (classical) or M2 (alternative) axis occurs during inflammation and can be at least partly categorized by the route of arginine metabolism within the macrophage, balancing the activities of the arginase and nitric oxide synthase (NOS) enzyme families (1, 2). Arginase activity is associated with tissue repair responses (via ornithine production and pro-proliferative effects). In contrast, NOS2 generates nitric oxide (NO) species with anti-proliferative effects that is necessary for protection against pathogens and aberrant cells (2, 3). Other NOS enzymes produce NO that acts in the regulation of smooth muscle tone and other cellular processes (4). Macrophages preferentially expressing the arginase or NOS2 pathways enzymes also influence T-cell activation, proliferation, signaling, and apoptosis in different ways (1).

While arginase and NOS enzymes can be used to ascertain the pathway of macrophage activation in rodents, there has been debate as to whether they are present in macrophages from humans and other mammals. The arginase and NOS enzymes are extensively conserved, and the NOS forms found in mammals are similar to those in cnidarians, mollusks, and other chordates (5, 6). These arginine-metabolizing enzymes are present in some human leukocytes, and there is evidence that they are also present in macrophages from other vertebrates, including chickens, rabbits, cows, and primates (7–12). However, comparisons of tissue macrophages of different species are lacking, which limits our understanding (13). Many studies in humans have principally focused on blood monocytes, leading some researchers to question the suitability of rodents as model of macrophage activation, as there is not always a direct correlation with human cells. Was Robert Koch correct when he said “Gentlemen, never forget that mice are not humans,” or can the differing results between species be explained, in part, by differences in the types of monocyte or macrophage studied? Our purpose here is to examine this question.