Evolution of M2 Macrophage Functions in Chordates

Abstract

Extant chordates are divided into three subphyla: tunicates (urochordates), cephalochordates, and vertebrates. Urochordates and vertebrates have macrophages, but cephalochordates are unique in their apparent lack of this cell type. Urochordate and nonmammalian vertebrate macrophages have M2-like functions, such as inhibition of macrophage-dependent cytotoxicity, wound healing, endocrine signaling, and clearance of apoptotic cell debris. However, signals of an M2-like activation in nonmammalian chordates are poorly understood, and we have major gaps in the principles of macrophage biology of some chordate phyla. For instance, studies are scarce in elasmobranch fishes, or in certain “living fossil” species, such as the axolotl, lungfish, or platypus. Moreover, the available data show that macrophage activation has unique features in some chordates that are distinct from the mammalian macrophage activation. For instance, macrophage activation is temperature dependent in sharks. In bony fishes, cAMP activates M2 macrophages, instead of an IL-4-equivalent protein; and there is a sexual dimorphism of macrophage functions in reptiles. This chapter provides a summary of these and other traits relevant for the understanding of M2 macrophage biology in chordates. Future studies of nonmammalian vertebrate macrophages can help us understand antitumor immunity, temperature- and light-sensitive changes in innate immune response, endocrine control of macrophage functions, disease control in aquaculture, and the role of macrophage activation in scar formation or regeneration.