The resolvin D1 receptor GPR32 transduces inflammation resolution and atheroprotection
The resolvin D1 receptor GPR32 transduces inflammation resolution and atheroprotection
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解决素D1受体GPR32转导炎症消退和动脉粥样硬化保护作用
DOI：
10.1172/jci142883
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发表时间：
2021-12-15
影响因子：
15.9
通讯作者：
Back, Magnus
中科院分区：
文献类型：
--
作者：
Arnardottir, Hildur;Thul, Silke;Back, Magnus
慢性炎症是动脉粥样硬化的一个标志，是促炎症和促溶解信号之间失衡的结果。人GPR32受体与ALX/FPR2受体一起转导几种促分解介质的生物学作用，从而刺激炎症的消退。然而，由于不存在人类GPR32受体的小鼠同源物，因此缺乏全面的体内研究。我们利用颈动脉内膜切除术中的人动脉粥样硬化病变，建立了在Fpr2xApoE双KO背景下表达人GPR32的转基因小鼠模型(hGPR32mycxFpr2(-/-)xApoe(-/-))，研究了GPR32在动脉粥样硬化和自限性急性炎症中的作用。GPR32mRNA在人类动脉粥样硬化病变中降低，并与免疫细胞标记物ARG1、NOS2和FOXP3相关。在hGPR32myc酵母多糖诱导的腹膜炎模型中，动脉粥样硬化病变、坏死灶和主动脉炎症明显减轻，hGPR32mycTgxFpr2(-/-)xApoe(-/-)转基因小鼠在4h时炎症反应减轻，24 h时巨噬细胞促分解反应增强。在hGPR32mycTgxFpr2(-/-)xApoe(-/-)转基因小鼠中，GPR32激动剂阿司匹林触发的解决素D1(AT-RvD1)调节白细胞反应，包括增强巨噬细胞吞噬和细胞内信号转导，但在Fpr2(-/-)xApoe(-/-)非转基因小鼠中不起作用。综上所述，这些结果提供了GPR32调节炎症消退并在体内具有动脉粥样硬化保护作用的证据。TgxFpr2(-/-)xApoe(-/-)转基因小鼠与Fpr2(-/-)xApoe(-/-)非转基因小鼠的比较。在一个
Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between proinflammatory and proresolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several proresolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 receptor exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2xApoE double KO background (hGPR32mycxFpr2(-/-)xApoe(-/-)), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2, and FOXP3. Atherosclerotic lesions, necrotic core, and aortic inflammation were reduced in hGPR32myc zymosan-induced peritonitis model, the hGPR32mycTgxFpr2(-/-)xApoe(-/-) transgenic mice had reduced inflammation at 4 hours and enhanced proresolving macrophage responses at 24 hours compared with nontransgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in hGPR32mycTgxFpr2(-/-)xApoe(-/-) transgenic mice, but not in Fpr2(-/-)xApoe(-/-) nontransgenic littermates. Together, these results provide evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo. TgxFpr2(-/-)xApoe(-/-) transgenic mice as compared with Fpr2(-/-)xApoe(-/-) nontransgenic littermates. In a