Abstract
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 CD11blow macrophages have metamorphed from M2-like macrophages, and modulated their protein profile to accommodate the changes in their function.
Highlights
Macrophages are highly plastic monocyte-derived cells that acquire different molecular and functional phenotypes following exposure to different bioactive molecules and environments
While some of the features of M2 differentiation, such as arginase-1 and 15-lipoxygenases expression, were 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
Since the major polarizing cytokines initially found to be involved in classical and alternative activation were derived from Th1 (IFNγ) and Th2 (IL-4 and IL-13) lymphocytes these activated macrophages were named M1 and M2, respectively
Summary
Macrophages are highly plastic monocyte-derived cells that acquire different molecular and functional phenotypes following exposure to different bioactive molecules and environments. EFFEROCYTOSIS AS AN ALTERNATIVE MODE OF MACROPHAGE ACTIVATION The recognition, engulfment, and responsiveness to apoptotic cells are cardinal properties of resident and inflammatory macrophages and play a role in processes, such as tissue morphogenesis and homeostasis, embryonic development, hematopoiesis, immunity, and the resolution of inflammation (Savill et al, 2002; Erwig and Henson, 2007; Ravichandran and Lorenz, 2007).
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