Deficiency of FAM3D (Family With Sequence Similarity 3, Member D), A Novel Chemokine, Attenuates Neutrophil Recruitment and Ameliorates Abdominal Aortic Aneurysm Development.
Deficiency of FAM3D (Family With Sequence Similarity 3, Member D), A Novel Chemokine, Attenuates Neutrophil Recruitment and Ameliorates Abdominal Aortic Aneurysm Development.
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缺乏 FAM3D（序列相似性 3 家族，成员 D），一种新型趋化因子，会减弱中性粒细胞的募集并改善腹主动脉瘤的发展
DOI：
10.1161/atvbaha.118.311289
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Kong W
中科院分区：
文献类型：
--
作者：
He L;Fu Y;Deng J;Shen Y;Wang Y;Yu F;Xie N;Chen Z;Hong T;Peng X;Li Q;Zhou J;Han J;Wang Y;Xi J;Kong W
补充数字内容可在文本中找到。趋化因子介导的中性粒细胞募集有助于腹主动脉瘤（AAA）的发病机制，并可能成为一个有前途的治疗靶点。FAM 3D（family with sequence similarity 3，member D）是最近发现的一种新的趋化因子。在这里，我们旨在探索FAM 3D在中性粒细胞募集和AAA发展中的作用。FAM 3D在人AAA组织以及弹性蛋白酶和CaPO 4诱导的小鼠腹主动脉瘤中显著上调。在两种小鼠模型中，FAM 3D缺陷显著减弱AAA的发展。流式细胞术分析表明，与野生型同窝小鼠相比，FAM 3D −/−小鼠在AAA形成的早期阶段主动脉中的中性粒细胞浸润减少。此外，通过腹腔注射应用FAM 3D中和抗体6D 7显著改善弹性蛋白酶诱导的AAA形成和中性粒细胞浸润。此外，与FAM 3D中和抗体6D 7的体外共培养实验和体内活体显微镜分析表明，内皮细胞衍生的FAM 3D诱导中性粒细胞募集。从机制上讲，FAM 3D上调并激活中性粒细胞中的Mac-1（巨噬细胞-1抗原），而FPR 1（甲酰肽受体1）或FPR 2的抑制显著阻断FAM 3D诱导的Mac-1激活，表明FAM 3D的作用依赖于两种FPR。此外，与Gi蛋白或β-arrestin相关的FPR信号传导的特异性抑制剂在体外抑制FAM 3D激活的Mac-1，而FAM 3D缺陷在体内降低中性粒细胞中FPR-Gi蛋白和β-arrestin信号传导的激活。FAM 3D作为FPR 1和FPR 2的双重激动剂，通过FPR相关的Gi蛋白和β-arrestin信号转导诱导Mac-1介导的中性粒细胞募集并加重AAA的发展。
Supplemental Digital Content is available in the text. Chemokine-mediated neutrophil recruitment contributes to the pathogenesis of abdominal aortic aneurysm (AAA) and may serve as a promising therapeutic target. FAM3D (family with sequence similarity 3, member D) is a recently identified novel chemokine. Here, we aimed to explore the role of FAM3D in neutrophil recruitment and AAA development. FAM3D was markedly upregulated in human AAA tissues, as well as both elastase- and CaPO4-induced mouse aneurysmal aortas. FAM3D deficiency significantly attenuated the development of AAA in both mouse models. Flow cytometry analysis indicated that FAM3D−/− mice exhibited decreased neutrophil infiltration in the aorta during the early stage of AAA formation compared with their wild-type littermates. Moreover, application of FAM3D-neutralizing antibody 6D7 through intraperitoneal injection markedly ameliorated elastase-induced AAA formation and neutrophil infiltration. Further, in vitro coculture experiments with FAM3D-neutralizing antibody 6D7 and in vivo intravital microscopic analysis indicated that endothelial cell–derived FAM3D induced neutrophil recruitment. Mechanistically, FAM3D upregulated and activated Mac-1 (macrophage-1 antigen) in neutrophils, whereas inhibition of FPR1 (formyl peptide receptor 1) or FPR2 significantly blocked FAM3D-induced Mac-1 activation, indicating that the effect of FAM3D was dependent on both FPRs. Moreover, specific inhibitors of FPR signaling related to Gi protein or β-arrestin inhibited FAM3D-activated Mac-1 in vitro, whereas FAM3D deficiency decreased the activation of both FPR-Gi protein and β-arrestin signaling in neutrophils in vivo. FAM3D, as a dual agonist of FPR1 and FPR2, induced Mac-1-mediated neutrophil recruitment and aggravated AAA development through FPR-related Gi protein and β-arrestin signaling.