PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock
PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock
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DOI：
10.1182/blood-2014-07-587709
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发表时间：
2015-03-19
期刊：
影响因子：
20.3
通讯作者：
Wagner, Denisa D.
中科院分区：
文献类型：
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作者：
Martinod, Kimberly;Fuchs, Tobias A.;Wagner, Denisa D.
中性粒细胞胞外陷阱(Net)是由含有组蛋白和杀微菌蛋白的核DNA组成的，在脓毒症期间从激活的中性粒细胞中排出。蚊帐被证明可以捕获微生物，但它们也会助长心血管疾病、血栓形成和自身免疫性疾病。Net在脓毒症中的作用，特别是它们的抗菌和细胞毒作用之间的平衡，仍然不清楚。对PAD4(-/-)缺陷小鼠的中性粒细胞进行了评估，这些小鼠缺乏允许染色质解缩和网状形成的酶。我们发现，参与细菌杀灭的中性粒细胞功能，而不是网织红细胞，仍然完好无损。因此，我们假设，防止网状物的形成可能不会对脓毒症产生毁灭性的后果。为了测试这一点，我们将PAD4(-/-)小鼠置于由盲肠结扎和穿孔产生的轻度和重度多菌败血症中。令人惊讶的是，在败血症条件下，PAD4(-/-)小鼠的表现并不比野生型小鼠差，而且存活率相当。在抗生素存在的情况下，PAD4缺乏导致略有加速的死亡率，但菌血症不受影响。PAD4(-/-)小鼠对内毒素休克有部分保护作用，提示PAD4/Net可能参与内毒素引起的毒性炎症和促凝血宿主反应。我们认为，在炎症性或血栓性疾病中通过抑制PAD4来防止网络形成不太可能增加宿主对细菌感染的易感性。
Neutrophil extracellular traps (NETs), consisting of nuclear DNA with histones and microbicidal proteins, are expelled from activated neutrophils during sepsis. NETs were shown to trap microbes, but they also fuel cardiovascular, thrombotic, and autoimmune disease. The role of NETs in sepsis, particularly the balance between their antimicrobial and cytotoxic actions, remains unclear. Neutrophils from peptidylarginine deiminase 4-(PAD4(-/-)) deficient mice, which lack the enzyme allowing for chromatin decondensation and NET formation, were evaluated. We found that neutrophil functions involved in bacterial killing, other than NETosis, remained intact. Therefore, we hypothesized that prevention of NET formation might not have devastating consequences in sepsis. To test this, we subjected the PAD4(-/-) mice to mild and severe polymicrobial sepsis produced by cecal ligation and puncture. Surprisingly, under septic conditions, PAD4(-/-) mice did not fare worse than wild-type mice and had comparable survival. In the presence of antibiotics, PAD4-deficiency resulted in slightly accelerated mortality but bacteremia was unaffected. PAD4(-/-) mice were partially protected from lipopolysaccharide-induced shock, suggesting that PAD4/NETs may contribute to the toxic inflammatory and procoagulant host response to endotoxin. We propose that preventing NET formation by PAD4 inhibition in inflammatory or thrombotic diseases is not likely to increase host vulnerability to bacterial infections.