The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation
The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation
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DOI：
10.1016/j.ajpath.2015.12.012
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发表时间：
2016-04-01
影响因子：
6
通讯作者：
Serhan, Charles N.
中科院分区：
文献类型：
--
作者：
Ramon, Sesquile;Dalli, Jesmond;Serhan, Charles N.
炎症及其自然消退是由感染或损伤引发的宿主保护反应。炎症的消退阶段是由酶产生的专门的促消退介质调节的。我们最近发现了一类新的肽偶联的特殊促分解介质，它们具有有效的组织再生作用，属于保护蛋白家族，被称为组织再生中的保护蛋白偶联物（PCTR）。本研究利用小鼠微生物性腹膜炎和基于液相色谱-串联质谱的脂质介质代谢脂质组学，发现PCTR1在自溶解感染过程中受到暂时调节。当在炎症高峰期给药时，PCTR1增强了巨噬细胞的募集和大肠杆菌的吞噬，减少了多形核白细胞的浸润，并抑制了炎症引发的脂质介质，包括前列腺素。此外，生物产生的PCTR1以剂量依赖性的方式促进人单核细胞和巨噬细胞的迁移（0.001至10.0 nmol/L）。我们通过有机合成的方法制备了PCTR1，并证实合成的PCTR1增加了涡虫中巨噬细胞和单核细胞的迁移，增强了巨噬细胞的efferocysis，加速了组织再生。在人巨噬细胞亚群中，M2型巨噬细胞中的PCTR1水平明显高于M1型，组织再生和maresin偶联家族中的resolvin偶联物成员也是如此。相比之下，M1巨噬细胞给予更高水平的半胱氨酸白三烯。总之，这些结果表明PCTR1是一种有效的单核细胞/巨噬细胞激动剂，在细菌感染过程中调节关键的抗炎和促溶解过程。
Inflammation and its natural resolution are host-protective responses triggered by infection or injury. The resolution phase of inflammation is regulated by enzymatically produced specialized pro-resolving mediators. We recently identified a new class of peptide-conjugated specialized pro-resolving mediators that carry potent tissue regenerative actions that belong to the protectin family and are coined protectin conjugates in tissue regeneration (PCTR). Herein, with the use of microbial-induced peritonitis in mice and liquid chromatography-tandem mass spectrometry-based lipid mediator metabololipidomics, we found that PCTR1 is temporally regulated during self-resolving infection. When administered at peak of inflammation, PCTR1 enhanced macrophage recruitment and phagocytosis of Escherichia coli, decreased polymorphonuclear Leukocyte infiltration, and counter-regulated inflammation-initiating lipid mediators, including prostaglandins. In addition, biologically produced PCTR1 promoted human monocyte and macrophage migration in a dose-dependent manner (0.001 to 10.0 nmol/L). We prepared PCTR1 via organic synthesis and confirmed that synthetic PCTR1 increased macrophage and monocyte migration, enhanced macrophage efferocytosis, and accelerated tissue regeneration in planaria. With human macrophage subsets, PCTR1 levels were significantly higher in M2 macrophages than in M1 phenotype, along with members of the resolvin conjugates in tissue regeneration and maresin conjugate families. In contrast, M1 macrophages gave higher levels of cysteinyl leukotrienes. Together, these results demonstrate that PCTR1 is a potent monocyte/macrophage agonist, regulating key anti-inflammatory and pro-resolving processes during bacterial infection.