Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice.
Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice.
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DOI：
10.1136/annrheumdis-2014-205365
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发表时间：
2015-12
影响因子：
27.4
通讯作者：
Kaplan MJ
中科院分区：
文献类型：
--
作者：
Knight JS;Subramanian V;O'Dell AA;Yalavarthi S;Zhao W;Smith CK;Hodgin JB;Thompson PR;Kaplan MJ
中性粒细胞胞外陷阱（NET）的形成和降解之间的不平衡已被描述在系统性红斑狼疮（SLE），可能有助于自身抗原外化，I型干扰素合成和内皮损伤。我们已经证明，肽基精氨酸脱亚胺酶（PAD）抑制减少NET的形成，并保护对狼疮相关的血管损伤在新西兰混合模型的狼疮。然而，另一种抑制NET敲除NOX 2的策略在不同的鼠模型MRL/lpr中加速狼疮。在这里，我们测试PAD抑制对MRL/lpr小鼠的影响，以澄清一些NET抑制途径是否可以在SLE模型中始终具有治疗性。NET的形成和自身抗体NET的特点是狼疮易感MRL/lpr小鼠。还用两种不同的PAD抑制剂Cl-脒和新描述的BB-Cl-脒处理MRL/lpr小鼠。NET形成，内皮功能，干扰素签名，肾炎和皮肤病进行了检查。与对照组相比，MRL/lpr小鼠的中性粒细胞显示出加速的NET形成。MRL/lpr小鼠还形成针对NET的自身抗体，并且具有内皮功能障碍的证据。PAD抑制显著改善内皮功能，同时下调I型干扰素调节基因的表达。PAD抑制还减少蛋白尿和免疫复合物在肾脏中的沉积，同时防止皮肤病。PAD抑制减少NET形成，同时在各种狼疮模型中保护血管系统、肾脏和皮肤免受狼疮相关损伤。如果要进行人体研究，就必须仔细考虑抑制NET的策略。
An imbalance between neutrophil extracellular trap (NET) formation and degradation has been described in systemic lupus erythematosus (SLE), potentially contributing to autoantigen externalisation, type I interferon synthesis and endothelial damage. We have demonstrated that peptidylarginine deiminase (PAD) inhibition reduces NET formation and protects against lupus-related vascular damage in the New Zealand Mixed model of lupus. However, another strategy for inhibiting NETs—knockout of NOX2—accelerates lupus in a different murine model, MRL/lpr. Here, we test the effects of PAD inhibition on MRL/lpr mice in order to clarify whether some NET inhibitory pathways may be consistently therapeutic across models of SLE. NET formation and autoantibodies to NETs were characterised in lupus-prone MRL/lpr mice. MRL/lpr mice were also treated with two different PAD inhibitors, Cl-amidine and the newly described BB-Cl-amidine. NET formation, endothelial function, interferon signature, nephritis and skin disease were examined in treated mice. Neutrophils from MRL/lpr mice demonstrate accelerated NET formation compared with controls. MRL/lpr mice also form autoantibodies to NETs and have evidence of endothelial dysfunction. PAD inhibition markedly improves endothelial function, while downregulating the expression of type I interferon-regulated genes. PAD inhibition also reduces proteinuria and immune complex deposition in the kidneys, while protecting against skin disease. PAD inhibition reduces NET formation, while protecting against lupus-related damage to the vasculature, kidneys and skin in various lupus models. The strategy by which NETs are inhibited will have to be carefully considered if human studies are to be undertaken.
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影响因子：
13.3
作者：
Kahlenberg, J. Michelle;Yalavarthi, Srilakshmi;Zhao, Wenpu;Hodgin, Jeffrey B.;Reed, Tamra J.;Tsuji, Noriko M.;Kaplan, Mariana J.
通讯作者：
Kaplan, Mariana J.
影响因子：
3.7
作者：
Hemmers S;Teijaro JR;Arandjelovic S;Mowen KA
通讯作者：
Mowen KA
影响因子：
5.3
作者：
AEBI, M;FAH, J;STAEHELI, P
通讯作者：
STAEHELI, P
影响因子：
3.6
作者：
Brothers, Shaun P.;Saldanha, S. Adrian;Hodder, Peter S.
通讯作者：
Hodder, Peter S.
DOI：
10.1111/j.1365-2133.2012.10825.x
发表时间：
2012-05
期刊：
The British journal of dermatology
影响因子：
--
作者：
Braunstein I;Klein R;Okawa J;Werth VP
通讯作者：
Werth VP