Activation of the Immune-Metabolic Receptor GPR84 Enhances Inflammation and Phagocytosis in Macrophages.
Activation of the Immune-Metabolic Receptor GPR84 Enhances Inflammation and Phagocytosis in Macrophages.
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DOI：
10.3389/fimmu.2018.01419
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发表时间：
2018
影响因子：
7.3
通讯作者：
Greaves DR
中科院分区：
文献类型：
--
作者：
Recio C;Lucy D;Purvis GSD;Iveson P;Zeboudj L;Iqbal AJ;Lin D;O'Callaghan C;Davison L;Griesbach E;Russell AJ;Wynne GM;Dib L;Monaco C;Greaves DR
GPR84是代谢G蛋白偶联受体家族的成员，其表达主要在免疫细胞中表达。GPR84激活参与了炎症反应，但它调节炎症的机制尚未完全描述。在这项研究中，我们研究了GPR84在巨噬细胞中的表达、激活和功能，以确定该受体在炎症反应中的作用。我们观察到内毒素血症、高血糖和高胆固醇血症会增加小鼠组织中GPR84的表达。体外研究表明，在不同的小鼠和人巨噬细胞群中，内毒素和其他促炎分子可以增加GPR84mRNA的表达。同样，高糖浓度和氧化低密度脂蛋白的存在增加了巨噬细胞中GPR84的表达。用选择性激动剂6-(辛氨基)-2，4(1H，3H)-二酮(6-正辛氨酸氨基尿嘧啶，6-非统)激活GPR84受体，可增强炎症条件下磷酸化Akt、p-ERK和p65的表达，并增加炎症介质肿瘤坏死因子α、IL-6、IL-12B、CCL2、CCL5和CXCL1的表达水平。此外，GPR84的激活引发了巨噬细胞内细菌黏附和吞噬功能的增加。在GPR84−/−细胞和经选择性GPR84拮抗剂处理的巨噬细胞中，均未观察到6-非统组织介导的炎症反应增强。总而言之，我们的结果显示，一旦炎症建立，GPR84在巨噬细胞中作为炎症信号的增强器发挥作用。因此，拮抗GPR84受体的分子可能成为炎症性和代谢性疾病的潜在治疗工具。
GPR84 is a member of the metabolic G protein-coupled receptor family, and its expression has been described predominantly in immune cells. GPR84 activation is involved in the inflammatory response, but the mechanisms by which it modulates inflammation have been incompletely described. In this study, we investigated GPR84 expression, activation, and function in macrophages to establish the role of the receptor during the inflammatory response. We observed that GPR84 expression in murine tissues is increased by endotoxemia, hyperglycemia, and hypercholesterolemia. Ex vivo studies revealed that GPR84 mRNA expression is increased by LPS and other pro-inflammatory molecules in different murine and human macrophage populations. Likewise, high glucose concentrations and the presence of oxidized LDL increased GPR84 expression in macrophages. Activation of the GPR84 receptor with a selective agonist, 6-(octylamino) pyrimidine-2,4(1H,3H)-dione (6-n-octylaminouracil, 6-OAU), enhanced the expression of phosphorylated Akt, p-ERK, and p65 nuclear translocation under inflammatory conditions and elevated the expression levels of the inflammatory mediators TNFα, IL-6, IL-12B, CCL2, CCL5, and CXCL1. In addition, GPR84 activation triggered increased bacterial adhesion and phagocytosis in macrophages. The enhanced inflammatory response mediated by 6-OAU was not observed in GPR84−/− cells nor in macrophages treated with a selective GPR84 antagonist. Collectively, our results reveal that GPR84 functions as an enhancer of inflammatory signaling in macrophages once inflammation is established. Therefore, molecules that antagonize the GPR84 receptor may be potential therapeutic tools in inflammatory and metabolic diseases.
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影响因子：
3.7
作者：
Iqbal AJ;Regan-Komito D;Christou I;White GE;McNeill E;Kenyon A;Taylor L;Kapellos TS;Fisher EA;Channon KM;Greaves DR
通讯作者：
Greaves DR
影响因子：
6.4
作者：
Davies LC;Taylor PR
通讯作者：
Taylor PR
影响因子：
5.8
作者：
Kapellos, Theodore S.;Taylor, Lewis;Lee, Heyne;Cowley, Sally A.;James, William S.;Iqbal, Asif J.;Greaves, David R.
通讯作者：
Greaves, David R.
影响因子：
3.5
作者：
Nagasaki, Hiroshi;Kondo, Takaaki;Hamada, Yoji
通讯作者：
Hamada, Yoji
作为有效 GPR84 激动剂的 2-烷基嘧啶-4,6-二醇和 6-烷基吡啶-2,4-二醇的设计和合成。
影响因子：
4.2
作者：
Liu, Yang;Zhang, Qing;Nan, Fa-Jun
通讯作者：
Nan, Fa-Jun