The constructive–repair–activity is commonly called M2 and the destructive–kill–activity of macrophages is called M1 [10, 14]. M2-and M1-type activities occur throughout the animal kingdom and are normally induced by macrophages sampling their environs for Damage-or Pathogen-Associated Molecular Patterns (DAMPs and PAMPs)[15]. By sensing whether to exhibit constructive or destructive activities macrophages are uniquely able to protect hosts in ways best suited to correcting varying non-infectious or infectious threats to hosts.

Macrophages were renamed M2/Heal and M1/Inhibit [14] in part because these repair or kill activities are associated with the production of Ornithine or Nitric Oxide, respectively, and other growth-promoting or growth–inhibiting molecules [4, 10]. Also, importantly, these very different innate protective activities do not require T cells/adaptive immunity, though macrophages can undergo further “activation”[16] or ‘alternative activation’[17] by antigen-specific T cells/adaptive immunity [10]. In this regard, M2/Heal and M1/Inhibittype activities precede the appearance of T cells/adaptive immunity in evolution by about 500 million years [1, 15]. In fact, the ability of cells to polarize functions is an evolutionarily ancient property even exhibited by single-celled animals such as amoeba [1, 18]. As mentioned, macrophages were the first leukocyte to evolve that specializes in protecting other cells [1].