Protein Deiminase 4 and CR3 Regulate Aspergillus fumigatus and β-Glucan-Induced Neutrophil Extracellular Trap Formation, but Hyphal Killing Is Dependent Only on CR3.
Protein Deiminase 4 and CR3 Regulate Aspergillus fumigatus and β-Glucan-Induced Neutrophil Extracellular Trap Formation, but Hyphal Killing Is Dependent Only on CR3.
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DOI：
10.3389/fimmu.2018.01182
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发表时间：
2018
影响因子：
7.3
通讯作者：
Pearlman E
中科院分区：
文献类型：
--
作者：
Clark HL;Abbondante S;Minns MS;Greenberg EN;Sun Y;Pearlman E
中性粒细胞胞外陷阱（NET）的形成需要在核肿胀和最终的细胞外DNA释放之前的染色质解凝聚，这与核和细胞质抗菌蛋白一起发生。染色质去凝聚的关键介质是蛋白脱亚胺酶4（PAD 4），其催化组蛋白瓜氨酸。在目前的研究中，我们研究了PAD 4和NETosis在A.烟曲霉菌丝提取物或细胞壁β-葡聚糖（可得兰），并发现两者均诱导人和鼠嗜中性粒细胞释放NET。此外，使用CR 3和Dectin-1的阻断抗体以及CR 3缺陷型CD 18 −/−和Dectin-1−/−小鼠中性粒细胞，我们发现β-葡聚糖受体CR 3而不是Dectin-1是NET形成所需的。NETosis也依赖于NADPH氧化酶产生的活性氧（ROS）。使用瓜氨酸化组蛋白3（H3Cit）的抗体作为PAD 4活性的指标，我们发现β-葡聚糖刺激的NETosis发生在C57 BL/6小鼠的中性粒细胞中，而不是PAD 4 −/−小鼠。类似地，小分子PAD 4抑制剂（GSK 484）阻断人嗜中性粒细胞的NET形成。尽管有这些观察结果，PAD 4 −/−中性粒细胞释放钙卫蛋白和杀死A.烟曲霉菌丝与C57 BL/6中性粒细胞没有显著差异，而CD 18 −/−中性粒细胞表现出执行这两种功能的能力受损。在A.烟曲霉感染C57 BL/6，但不感染PAD 4 −/−角膜;然而，我们发现C57 BL/6和PAD 4 −/−小鼠在角膜疾病或菌丝杀灭方面没有差异。综上所述，这些发现使我们得出结论，虽然PAD 4和CR 3介导的ROS的产生是需要NET形成响应A。烟曲霉不需要依赖于PAD 4的NETosis。烟曲霉在体外或感染期间均可杀死。
Neutrophil extracellular trap (NET) formation requires chromatin decondensation before nuclear swelling and eventual extracellular release of DNA, which occurs together with nuclear and cytoplasmic antimicrobial proteins. A key mediator of chromatin decondensation is protein deiminase 4 (PAD4), which catalyzes histone citrullination. In the current study, we examined the role of PAD4 and NETosis following activation of neutrophils by A. fumigatus hyphal extract or cell wall β-glucan (curdlan) and found that both induced NET release by human and murine neutrophils. Also, using blocking antibodies to CR3 and Dectin-1 together with CR3-deficient CD18−/− and Dectin-1−/− murine neutrophils, we found that the β-glucan receptor CR3, but not Dectin-1, was required for NET formation. NETosis was also dependent on NADPH oxidase production of reactive oxygen species (ROS). Using an antibody to citrullinated histone 3 (H3Cit) as an indicator of PAD4 activity, we show that β-glucan stimulated NETosis occurs in neutrophils from C57BL/6, but not PAD4−/− mice. Similarly, a small molecule PAD4 inhibitor (GSK484) blocked NET formation by human neutrophils. Despite these observations, the ability of PAD4−/− neutrophils to release calprotectin and kill A. fumigatus hyphae was not significantly different from C57BL/6 neutrophils, whereas CD18−/− neutrophils exhibited an impaired ability to perform both functions. We also detected H3Cit in A. fumigatus infected C57BL/6, but not PAD4−/− corneas; however, we found no difference between C57BL/6 and PAD4−/− mice in either corneal disease or hyphal killing. Taken together, these findings lead us to conclude that although PAD4 together with CR3-mediated ROS production is required for NET formation in response to A. fumigatus, PAD4-dependent NETosis is not required for A. fumigatus killing either in vitro or during infection.
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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：
5.2
作者：
Kenno S;Perito S;Mosci P;Vecchiarelli A;Monari C
通讯作者：
Monari C
影响因子：
6.7
作者：
Bruns S;Kniemeyer O;Hasenberg M;Aimanianda V;Nietzsche S;Thywissen A;Jeron A;Latgé JP;Brakhage AA;Gunzer M
通讯作者：
Gunzer M
影响因子：
7.3
作者：
Konig MF;Andrade F
通讯作者：
Andrade F