Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD; and.
Center for Bioinformatics and Computational Biology, University of Maryland Institute for Advanced Computer Studies, College Park, MD.
Blood Adv. 2020 Nov 10;4(21):5460-5472. doi: 10.1182/bloodadvances.2020002683.
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.
被刺激的巨噬细胞是炎症介质的有力产生者。这种活性受到高度调节，部分原因是通过解决分子来防止组织损伤。在这项研究中，我们证明了 Toll 样受体刺激引起的炎症会导致腺苷（Ado）和前列腺素 E2（PGE2）受体的上调，这有助于终止巨噬细胞的激活并启动组织重塑和血管生成。巨噬细胞可以从单核细胞中造血衍生而来，以响应 2 种生长因子：巨噬细胞集落刺激因子（M-CSF）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）。我们研究了暴露于这些分化因子中的任何一种如何塑造巨噬细胞对解决分子的反应。我们分析了在 Ado 或 PGE2 存在下刺激的人单核细胞衍生的巨噬细胞的转录组，证明在 M-CSF 分化的巨噬细胞中，Ado 和 PGE2 诱导涉及炎症介质下调和生长因子上调的共享转录程序。相比之下，在 GM-CSF 中生成的巨噬细胞不能转化为促进生长的表型，我们将其归因于 Ado 和 PGE2 受体的抑制和这些内源性调节剂的产量较低。这些观察结果表明，M-CSF 巨噬细胞更适合过渡到组织修复程序，而 GM-CSF 巨噬细胞经历更深刻的激活。我们认为对促解决介质的敏感性差异是这些不同表型的原因之一。这项研究强调了许多可以用来调节巨噬细胞激活的强度和持续时间的分子靶标。
