Hemin impairs resolution of inflammation via microRNA-144-3p-dependent downregulation of ALX/FPR2
Hemin impairs resolution of inflammation via microRNA-144-3p-dependent downregulation of ALX/FPR2
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DOI：
10.1111/trf.14991
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发表时间：
2019-01-01
期刊：
影响因子：
2.9
通讯作者：
Wen, Aiqing
中科院分区：
文献类型：
--
作者：
Sun, Guixiang;Lu, Yao;Wen, Aiqing
背景：输血并发症的病理机制尚不完全清楚。储存的红细胞中血红素水平升高被认为与输血反应，尤其是炎症反应有关。最近，血红素的促炎作用已被广泛研究。然而，血红素是否能影响炎症消退这一炎症反应的关键步骤尚不清楚。研究设计和方法：采用小鼠自限性腹膜炎模型，通过消退指数评估消退情况。采用蛋白质印迹、定量逆转录酶聚合酶链反应、趋化性测定、荧光素酶报告基因测定和慢病毒感染来研究中性粒细胞可能的介导机制。结果：腹腔注射氯化血红素显着增加了小鼠腹膜炎的白细胞浸润，并使缓解间隔延长了约7小时。在体外，氯高铁血红素显着下调 ALX/FPR2 蛋白水平 (p < 0.05)，这是一种关键的解析受体，从而抑制由促解析配体 resolvin D1 触发的促解析反应。随后，通过预测数据库选择的 miR-144-3p 被发现被氯化血红素显着上调 (p < 0.05)。 miR-144-3p 的抑制减弱了氯高铁血红素对脂氧素 A(4) 受体 (ALX)/甲酰肽受体 2 (FPR2) 蛋白表达的抑制作用 (p < 0.05)。荧光素酶报告基因测定证实 miR-144-3p 直接结合 ALX/FPR2 3'-UTR。 miR-144-3p 过表达显着下调 ALX/FPR2 蛋白水平，而 miR-144-3p 抑制导致 ALX/FPR2 显着增加 (p < 0.05)。 结论：我们的结果表明，氯化血红素可延长自限性炎症的消退时间，这种作用与氯化血红素诱导的 miR-144-3p 介导的 ALX/FPR2 下调相关。这些发现证明了源自储存红细胞的血红素用于炎症反应的新机制。
BACKGROUND: The pathomechanisms of complications due to blood transfusion are not fully understood. Elevated levels of heme derived from stored RBCs are thought to be associated with transfusion reactions, especially inflammatory responses. Recently, the proinflammatory effect of heme has been widely studied. However, it is still unknown whether heme can influence the resolution of inflammation, a key step of inflammatory response.STUDY DESIGN AND METHODS: A murine model of self-limited peritonitis was used, and resolution was assessed by resolution indices. Western blot, quantitative reverse transcriptase polymerase chain reaction, chemotaxis assay, luciferase reporter assay, and lentivirus infections were used to investigate possible mediating mechanisms in neutrophils.RESULTS: The administration of hemin by intraperitoneal injection significantly increased the leukocyte infiltration and prolonged the resolution interval by approximately 7 hours in mouse peritonitis. In vitro, hemin significantly downregulated ALX/FPR2 protein levels (p < 0.05), a key resolution receptor, leading to the suppression of proresolution responses triggered by the proresolution ligand resolvin D1. Subsequently, miR-144-3p, selected by prediction databases, was found to be significantly upregulated by hemin (p < 0.05). The inhibition of miR-144-3p attenuated the inhibitory effect of hemin on lipoxin A(4) receptor (ALX)/formyl peptide receptor 2 (FPR2) protein expression (p < 0.05). Luciferase reporter assay confirmed that miR-144-3p directly bound ALX/FPR2 3'-UTR. MiR-144-3p overexpression significantly downregulated ALX/FPR2 protein levels, whereas miR-144-3p inhibition led to a significant increase in ALX/FPR2 (p < 0.05).CONCLUSION: Our results suggest that hemin prolongs resolution in self-limited inflammation, and this action is associated with downregulation of ALX/FPR2 mediated by hemin-induced miR-144-3p. These findings demonstrate a novel mechanism of hemin derived from stored RBCs for inflammatory response.