Prostaglandin E2 and Its Receptor EP2 Modulate Macrophage Activation and Fusion in Vitro
Prostaglandin E2 and Its Receptor EP2 Modulate Macrophage Activation and Fusion in Vitro
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DOI：
10.1021/acsbiomaterials.9b01180
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发表时间：
2020-05-01
影响因子：
5.8
通讯作者：
Bryant, Stephanie J.
中科院分区：
文献类型：
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作者：
Saleh, Leila S.;Vanderheyden, Casey;Bryant, Stephanie J.
异物反应(FBR)通过其慢性炎症和异物巨细胞(FBGC)的形成导致纤维包裹，阻碍了新型植入式医疗器械的发展。已知巨噬细胞驱动FBR，但控制巨噬细胞极化的努力仍然具有挑战性。本研究的目的是研究前列腺素E2(PGE2)，特别是其受体EP2和/或EP4，是否在体外减弱经典激活(即炎症)的巨噬细胞和巨噬细胞与FBGCs的融合。经PGE2处理后，脂多糖(LPS)刺激的巨噬细胞肿瘤坏死因子-α(TNF-α)基因表达和蛋白产量呈剂量依赖性下降。这种抑制主要是通过EP4受体实现的，因为在PGE_2刺激的细胞中加入EP2拮抗剂PF 04418948并不能恢复肿瘤坏死因子-α的产生，而EP4拮抗剂Ono AE3208可以。然而，用激动剂丁前列素直接刺激EP2对内毒素刺激的巨噬细胞，4h后肿瘤坏死因子-α的分泌减少约60%，与CEBPB和IL10的基因表达增加相对应，这表明极化转变为单独通过EP2的交替激活。此外，PGE2通过EP2信号通路和EP2激动剂抑制白细胞介素4(IL-4)和粒细胞巨噬细胞集落刺激因子(GM-CSF)诱导的巨噬细胞与FBGCs的融合，但不抑制EP4激动剂。PGE2的抑制作用主要是通过EP2受体实现的。在IL-4/GM-CSF刺激下，MRc1、Dcstamp和Retina的表达增加，但只有在EP2激动剂作用下Retnla的表达恢复到与对照组相同的水平。这项研究发现，PGE2通过不同的EP受体减弱经典激活的巨噬细胞和巨噬细胞融合，而靶向EP2能够减弱两者。综上所述，这项研究确定EP2是将FBR减少为生物材料的潜在治疗靶点。
The foreign body response (FBR) has impaired progress of new implantable medical devices through its hallmark of chronic inflammation and foreign body giant cell (FBGC) formation leading to fibrous encapsulation. Macrophages are known to drive the FBR, but efforts to control macrophage polarization remain challenging. The goal for this study was to investigate whether prostaglandin E2 (PGE2), and specifically its receptors EP2 and/or EP4, attenuate classically activated (i.e., inflammatory) macrophages and macrophage fusion into FBGCs in vitro. Lipopolysaccharide (LPS)-stimulated macrophages exhibited a dose-dependent decrease in gene expression and protein production of tumor necrosis factor alpha (TNF-alpha) when treated with PGE2. This attenuation was primarily by the EP4 receptor, as the addition of the EP2 antagonist PF 04418948 to PGE2-treated LPS-stimulated cells did not recover TNF-alpha production while the EP4 antagonist ONO AE3 208 did. However, direct stimulation of EP2 with the agonist butaprost to LPS-stimulated macrophages resulted in a similar to 60% decrease in TNF-alpha secretion after 4 h and corresponded with an increase in gene expression for Cebpb and Il10, suggesting a polarization shift toward alternative activation through EP2 alone. Further, fusion of macrophages into FBGCs induced by interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was inhibited by PGE2 via EP2 signaling and by an EP2 agonist, but not an EP4 agonist. The attenuation by PGE2 was confirmed to be primarily by the EP2 receptor. Mrc1, Dcstamp, and Retina expressions increased upon IL-4/GM-CSF stimulation, but only Retnla expression with the EP2 agonist returned to levels that were not different from controls. This study identified that PGE2 attenuates classically activated macrophages and macrophage fusion through distinct EP receptors, while targeting EP2 is able to attenuate both. In summary, this study identified EP2 as a potential therapeutic target for reducing the FBR to biomaterials.