Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis.
Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis.
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DOI：
10.3389/fimmu.2018.01680
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发表时间：
2018
影响因子：
7.3
通讯作者：
Kaplan MJ
中科院分区：
文献类型：
--
作者：
Liu Y;Carmona-Rivera C;Moore E;Seto NL;Knight JS;Pryor M;Yang ZH;Hemmers S;Remaley AT;Mowen KA;Kaplan MJ
越来越多的证据表明，中性粒细胞胞外陷阱（NET）可能在促进人类和小鼠模型动脉粥样硬化斑块病变中发挥作用。NET驱动的动脉粥样硬化形成中涉及的确切途径仍有待系统表征。为了评估骨髓特异性肽基精氨酸脱亚胺酶4（PAD 4）和PAD 4依赖性NET形成对动脉粥样硬化的影响程度，产生了骨髓特异性PAD 4缺失的小鼠，并与Apoe−/−小鼠回交。测定动脉粥样硬化发展的动力学。NET，而不是巨噬细胞胞外陷阱，出现在动脉粥样硬化病变后3周开始高脂食物。NET的存在与动脉粥样硬化的发展和主动脉中的炎症反应有关。髓系中PAD 4的特异性缺失显著降低了动脉粥样硬化负荷，这与NET形成减少和主动脉炎症反应减少有关。NET刺激巨噬细胞合成炎症介质，包括IL-1β、CCL 2、CXCL 1和CXCL 2。我们的数据支持NET促进动脉粥样硬化的观点，并且使用特定的PAD 4抑制剂可能在这种潜在的破坏性疾病中具有治疗益处。
Increasing evidence suggests that neutrophil extracellular traps (NETs) may play a role in promoting atherosclerotic plaque lesions in humans and in murine models. The exact pathways involved in NET-driven atherogenesis remain to be systematically characterized. To assess the extent to which myeloid-specific peptidylarginine deiminase 4 (PAD4) and PAD4-dependent NET formation contribute to atherosclerosis, mice with myeloid-specific deletion of PAD4 were generated and backcrossed to Apoe−/− mice. The kinetics of atherosclerosis development were determined. NETs, but not macrophage extracellular traps, were present in atherosclerotic lesions as early as 3 weeks after initiating high-fat chow. The presence of NETs was associated with the development of atherosclerosis and with inflammatory responses in the aorta. Specific deletion of PAD4 in the myeloid lineage significantly reduced atherosclerosis burden in association with diminished NET formation and reduced inflammatory responses in the aorta. NETs stimulated macrophages to synthesize inflammatory mediators, including IL-1β, CCL2, CXCL1, and CXCL2. Our data support the notion that NETs promote atherosclerosis and that the use of specific PAD4 inhibitors may have therapeutic benefits in this potentially devastating condition.
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影响因子：
3.7
作者：
Hemmers S;Teijaro JR;Arandjelovic S;Mowen KA
通讯作者：
Mowen KA
DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
影响因子：
20.1
作者：
Drechsler M;de Jong R;Rossaint J;Viola JR;Leoni G;Wang JM;Grommes J;Hinkel R;Kupatt C;Weber C;Döring Y;Zarbock A;Soehnlein O
通讯作者：
Soehnlein O
影响因子：
27.4
作者：
Knight JS;Subramanian V;O'Dell AA;Yalavarthi S;Zhao W;Smith CK;Hodgin JB;Thompson PR;Kaplan MJ
通讯作者：
Kaplan MJ
影响因子：
29.4
作者：
Merza, Mohammed;Hartman, Hannes;Thorlacius, Henrik
通讯作者：
Thorlacius, Henrik