Neutrophil Extracellular Traps Sustain Inflammatory Signals in Ulcerative Colitis
Neutrophil Extracellular Traps Sustain Inflammatory Signals in Ulcerative Colitis
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DOI：
10.1093/ecco-jcc/jjy215
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发表时间：
2019-06-01
影响因子：
8
通讯作者：
Monteleone, Giovanni
中科院分区：
文献类型：
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作者：
Dinallo, Vincenzo;Marafini, Irene;Monteleone, Giovanni
背景和目的在溃疡性结肠炎[UC]中，粘膜损伤发生在中性粒细胞浸润的区域。中性粒细胞的抗菌功能部分依赖于细胞外网状结构的形成，称为中性粒细胞胞外陷阱[NETs]。异常NETs的形成和/或清除与几种免疫疾病有关。在这里，我们研究了NETs在uc相关炎症中的作用。方法采用Western blotting、免疫荧光和免疫组织化学方法对克罗恩病（CD）、UC和正常对照（NC）患者结肠活检组织中net相关蛋白的表达进行检测。分析抗肿瘤坏死因子治疗前后UC患者的结肠活检。在体外测试了中性粒细胞在激活后产生NETs的能力。UC固有层单核细胞（LPMCs）用NETs培养，在存在或不存在细胞外信号调节激酶1/2 （ERK1/2）抑制剂的情况下，通过实时聚合酶链反应和酶联免疫吸附法评估炎症细胞因子的诱导作用。我们还描述了NETs在葡聚糖硫酸钠（DSS）诱导的结肠炎中的作用。结果与CD患者和NC患者相比，UC患者炎症结肠中net相关蛋白过表达。UC患者的循环中性粒细胞在TNF-刺激下产生NETs，在接受抗TNF-成功治疗的患者中，NET相关蛋白的表达减少，NET形成减少。用NETs治疗UC lpmc激活ERK1/2，从而增强TNF-和白细胞介素-1 [IL-1]的产生。在dss -结肠炎小鼠中诱导NETs，并在体内抑制NETs释放减轻结肠炎。我们的数据表明，NET释放发生在UC中，并提示NETs在这种疾病中维持粘膜炎症的作用。
Background and Aims In ulcerative colitis [UC], mucosal damage occurs in areas that are infiltrated with neutrophils. The antimicrobial function of neutrophils relies in part on the formation of extracellular web-like structures, named neutrophil extracellular traps [NETs]. The formation and/or clearance of aberrant NETs have been associated with several immune diseases. Here we investigated the role of NETs in UC-related inflammation.Methods The expression of NET-associated proteins was evaluated in colonic biopsies of patients with Crohn's disease [CD], UC and in normal controls [NC] by Western blotting, immunofluorescence and immunohistochemistry. Colonic biopsies of UC patients were analysed before and after anti-tumour necrosis factor [anti-TNF-] treatment. The capacity of neutrophils to produce NETs upon activation was tested in vitro. UC lamina propria mononuclear cells [LPMCs] were cultured with NETs in the presence or absence of an extracellular signal-regulated kinase-1/2 [ERK1/2] inhibitor and inflammatory cytokine induction was assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. We also characterized the contribution of NETs in dextran sodium sulfate [DSS]-induced colitis.Results NET-associated proteins were over-expressed in inflamed colon of UC patients as compared to CD patients and NC. Circulating neutrophils of UC patients produced NETs in response to TNF- stimulation, and reduced expression of NET-related proteins and diminished NET formation were seen in patients receiving successful treatment with anti-TNF-. Treatment of UC LPMCs with NETs activated ERK1/2, thus enhancing TNF- and interleukin-1 [IL-1] production. NETs were induced in mice with DSS-colitis and in vivo inhibition of NET release attenuated colitis.Conclusions Our data show that NET release occurs in UC and suggest a role for NETs in sustaining mucosal inflammation in this disorder.