A

B

C

C

D

 

Early responses to pathogens or trauma are executed by type 1-like macrophages prior to encounter with apoptotic PMNs (A). Upon tethering and engulfment of cell corpses (early efferocytosis), the macrophage switches to a type 2-like phenotype that counters inflammation while being intensely involved in efferocytosis, tissue repair, and return to homeostasis. Importantly, type 2 macrophages can also promote fibrosis and scar formation and exert a proliferative potential (B). As the engulfment of apoptotic PMNs 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 MMP-9 (a protease involved in the release and activation of TGFβ) and display reduced phagocytosis of extracellular particles including apoptotic cells. Consequently, Mres exit the resolving tissue and reach lymphoid organs and other target tissues. At these remote sites, Mres presumably produce 12/15-LO-derived pro-resolving lipid mediators and deliver homeostatic signals to antigen-presenting cells and lymphocytes. Mres are probably more resistant to apoptosis and more amenable to proliferate and thereby enhance their immunoregulatory impact. 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 and intermediates in their production 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 soluble pro-resolving and anti-inflammatory mediators, such as lipoxins, resolvins, protectins, maresin, GCs, IL-4, TGFβ, IL-10, CCL2, and PPARγ ligands, or by apoptotic cell surface-expressed D6, proteinase 3, and calreticulin (D, E). As a result, the reprogramming and departure of Mres to the lymphatics may be adjusted to impact the termination of acquired immune response

(Ariel & Timor, 2013, Journal of Pathology 2013;229:250-63).