Abstract
Stimulated macrophages are potent producers of inflammatory mediators. This activity is highly regulated, in part, by resolving molecules to prevent tissue damage. In this study, we demonstrate that inflammation induced by Toll-like receptor stimulation is followed by the upregulation of receptors for adenosine (Ado) and prostaglandin E2 (PGE2), which help terminate macrophage activation and initiate tissue remodeling and angiogenesis. Macrophages can be hematopoietically derived from monocytes in response to 2 growth factors: macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We examine how exposure to either of these differentiation factors shapes the macrophage response to resolving molecules. We analyzed the transcriptomes of human monocyte-derived macrophages stimulated in the presence of Ado or PGE2 and demonstrated that, in macrophages differentiated in M-CSF, Ado and PGE2 induce a shared transcriptional program involving the downregulation of inflammatory mediators and the upregulation of growth factors. In contrast, macrophages generated in GM-CSF fail to convert to a growth-promoting phenotype, which we attribute to the suppression of receptors for Ado and PGE2 and lower production of these endogenous regulators. These observations indicate that M-CSF macrophages are better prepared to transition to a program of tissue repair, whereas GM-CSF macrophages undergo more profound activation. We implicate the differential sensitivity to pro-resolving mediators as a contributor to these divergent phenotypes. This research highlights a number of molecular targets that can be exploited to regulate the strength and duration of macrophage activation.