New Lives Given by Cell Death: Macrophage Differentiation Following Their Encounter with Apoptotic Leukocytes during the Resolution of Inflammation

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 CD11b(low) macrophages have metamorphed from M2-like macrophages, and modulated their protein profile to accommodate the changes in their function.

Keywords: efferocytosis; macrophage differentiation; pro-resolving lipid mediators; resolution of inflammation.

Figure 1

Macrophage phenotype conversions induced by efferocytosis. A monocyte that infiltrated an inflamed tissue differentiates to a macrophage and adopts an M1-like phenotype previous to encounter with apoptotic PMNs (A). Once it encounters apoptotic PMN and starts to engulf them (early efferocytosis), the macrophage switches to an M2-like phenotype that is anti-inflammatory, highly efferocytic, and involved in tissue repair and return to homeostasis, but can also promote fibrosis and scar formation (B). As the engulfment of apoptotic PMN by the macrophage continues and reaches a threshold level determined by the resolving milieu (satiating-efferocytosis) the macrophage undergoes another switch to the Mres phenotype (C). These macrophages reduce the expression of pro-fibrotic arginase-1 and display reduced phagocytosis of extracellular particle including apoptotic cells. Consequently, rapid Mres departure of the resolving tissue and emigration to remote sites takes place. At these target organs Mres macrophages presumably produce 12/15-LO-derived pro-resolving lipid mediators, and deliver homeostatic signals to antigen presenting cells and lymphocytes. Moreover, Mres that stay in the resolving tissue might express higher levels of anti-inflammatory, anti-fibrotic, and anti-oxidant proteins to limit tissue damage and fibrosis. 12/15-LO-derived lipid mediators probably also contribute to the anti-inflammatory and anti-fibrotic properties of Mres in the resolving tissue. Early and satiating-efferocytosis can be modulated by pro-resolving and anti-inflammatory mediators, such as lipoxins, resolvins, protectins, maresin, GC, IL-4, TGFβ, IL-10, and PPARγ ligands (D). This modulation can enhance the immune-silencing and departure of Mres to the lymphatics, where they can contribute to the termination of acquired immune responses.