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PAD4-dependent NETs generation are indispensable for intestinal clearance of Citrobacter rodentium.
Mucosal Immunology ( IF 8 ) Pub Date : 2019-02-01 , DOI: 10.1038/s41385-019-0139-3
Piu Saha 1 , Beng San Yeoh 2 , Xia Xiao 3 , Rachel M Golonka 1 , Vishal Singh 1 , Yanming Wang 4 , Matam Vijay-Kumar 1
Affiliation  

Peptidyl arginine deiminase-4 (PAD4) is indispensable for generation of neutrophil extracellular traps (NETs), which can provide antimicrobial effects during host innate immune response; however, the role of PAD4 against gastrointestinal infection is largely unknown. Herein, we challenged PAD4-deficient (Pad4-/-) mice and wild-type (WT) littermates with Citrobacter rodentium (CR), and investigated bacteria clearance and gut pathology. Luminal colonization of CR in Pad4-/- mice peaked between 11-14 days post-infection, whereas WT mice suppressed the infection by 14 days. We demonstrated that Pad4-/- mice were unable to form NETs, whereas WT mice showed increased NETs formation in the colon during infection. Pad4-/- mice showed aggravated CR-associated inflammation as indicated by elevated systemic and colonic pro-inflammatory markers. Histological analysis revealed that transmissible colonic hyperplasia, goblet cell depletion, and apoptotic cell death were more pronounced in the colon of CR-infected Pad4-/- mice. Treating WT mice with deoxyribonuclease I, which can disrupt NETs generation, recapitulated the exacerbated CR infection and gut pathology associated with the loss of PAD4. Administration of the PAD4 inhibitor, Cl-amidine also aggravated CR infection, but to a lesser extent. Taken together, our findings highlight the importance of PAD4 in the mucosal clearance of CR and in resolving gut-associated inflammation.

中文翻译:

PAD4 依赖性 NET 的产生对于啮齿类柠檬酸杆菌的肠道清除是必不可少的。

肽基精氨酸脱亚胺酶 4 (PAD4) 对于中性粒细胞胞外陷阱 (NET) 的生成是不可或缺的,它可以在宿主先天免疫反应期间提供抗菌作用;然而,PAD4 对抗胃肠道感染的作用尚不清楚。在此,我们用啮齿类柠檬酸杆菌 (CR) 攻击 PAD4 缺陷 (Pad4-/-) 小鼠和野生型 (WT) 小鼠,并研究细菌清除和肠道病理学。Pad4-/- 小鼠中 CR 的管腔定植在感染后 11-14 天之间达到峰值,而 WT 小鼠则将感染抑制了 14 天。我们证明 Pad4-/- 小鼠无法形成 NETs,而 WT 小鼠在感染期间结肠中的 NETs 形成增加。Pad4-/- 小鼠表现出严重的 CR 相关炎症,如全身和结肠促炎标记物升高所示。组织学分析显示,在 CR 感染的 Pad4-/- 小鼠的结肠中,传染性结肠增生、杯状细胞耗竭和细胞凋亡更为明显。用脱氧核糖核酸酶 I 治疗 WT 小鼠,可以破坏 NET 的生成,重现了与 PAD4 缺失相关的 CR 感染加剧和肠道病理学变化。使用 PAD4 抑制剂 Cl-脒也会加重 CR 感染,但程度较轻。总而言之,我们的研究结果强调了 PAD4 在 CR 粘膜清除和解决肠道相关炎症中的重要性。
更新日期:2019-07-05
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