New lives given by cell death: macrophage differentiation following their encounter with apoptotic leukocytes during the resolution of inflammation

Monocytes that migrate into tissues during inflammatory episodes and differentiate to macrophages were previously classified as classically (M1) or alternatively (M2) activated macrophages, based on their exposure to different fate-determining mediators. These macrophage subsets display distinct molecular markers and differential functions. At the same time, studies from recent years found that the encounter of apoptotic leukocytes with macrophages leads to the clearance of this cellular debris by the macrophages, while concomitantly reprogramming/immune-silencing the macrophages. While some of the features of M2 differentiation, such as arginase-1 (murine) and 15-lipoxygenases (human and murine) expression, were also displayed by macrophages following the engulfment of apoptotic cells, it was not clear whether apoptotic cells can be regarded as an M2-like differentiating signal. In this manuscript we review the recent information regarding the impact of apoptotic cells on macrophage phenotype changes in molecular terms. We will focus on recent evidence for the in vivo existence of distinct pro-resolving macrophages and the role of apoptotic cells, specialized lipid mediators, and glucocorticoids in their generation. Consequently, we will suggest that these pro-resolving CD11b(low) macrophages have meta-morphed from M2-like macrophages, and modulated their protein profile to accommodate the changes in their function.