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A C-terminal fragment of adhesion protein Fibulin7 regulates neutrophil migration and functions and improves survival in LPS induced systemic inflammation
Cytokine ( IF 3.8 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.cyto.2020.155113
Papiya Chakraborty 1 , Nibedita Dalpati 1 , Chandra Bhan 1 , Shiba Prasad Dash 1 , Puneet Kumar 1 , Pranita P Sarangi 1
Affiliation  

Accumulation of hyperactive neutrophils in the visceral organs was shown to be associated with sepsis-induced multi-organ failure. Recently, a C-terminal fragment of secreted glycoprotein Fibulin7 (Fbln7-C) was shown to inhibit angiogenesis and regulate monocyte functions in inflammatory conditions. However, its effects on neutrophil functions and systemic inflammation induced lethality remain unknown. In this study, we show that human peripheral blood neutrophils adhered to Fbln7-C in a dose-dependent manner via integrin β1. Moreover, the presence of Fbln7-C inhibited spreading, and fMLP mediated random migration of neutrophils on fibronectin. Significant reduction in ROS and inflammatory cytokine production (i.e., IL-6, IL-1β) was observed, including a reduction in ERK1⁄2 phosphorylation in neutrophils stimulated with LPS and fMLP in the presence of Fbln7-C compared to untreated controls. In an in vivo model of endotoxemia, the administration of Fbln7-C (10 μg/dose) significantly improved survival and reduced the infiltration of neutrophils to the site of inflammation. Additionally, neutrophils infiltrating into the inflamed peritoneum of Fbln7-C administered animals expressed lower levels CD11b marker, IL-6, and produced lower levels of ROS upon stimulation with PMA compared to untreated controls. In conclusion, our results show that Fbln7-C could bind to the integrin β1 on the neutrophil surface and regulate their inflammatory functions.

中文翻译:

粘附蛋白 Fibulin7 的 C 端片段调节中性粒细胞迁移和功能并提高 LPS 诱导的全身炎症的存活率

内脏器官中过度活跃的中性粒细胞的积累被证明与败血症引起的多器官衰竭有关。最近,分泌性糖蛋白 Fibulin7 (Fbln7-C) 的 C 端片段显示可抑制血管生成并调节炎症条件下的单核细胞功能。然而,其对中性粒细胞功能和全身炎症诱导的致死率的影响仍然未知。在这项研究中,我们表明人外周血中性粒细胞通过整合素 β1 以剂量依赖性方式粘附于 Fbln7-C。此外,Fbln7-C 的存在抑制了扩散,fMLP 介导了嗜中性粒细胞在纤连蛋白上的随机迁移。观察到 ROS 和炎性细胞因子的产生(即 IL-6、IL-1β)显着减少,包括与未处理的对照相比,在 Fbln7-C 存在下用 LPS 和 fMLP 刺激的中性粒细胞的 ERK1⁄2 磷酸化减少。在体内毒素血症模型中,Fbln7-C(10 μg/剂量)的给药显着提高了存活率并减少了嗜中性粒细胞对炎症部位的浸润。此外,与未治疗的对照相比,浸润到 Fbln7-C 给药动物发炎腹膜中的中性粒细胞表达较低水平的 CD11b 标记物 IL-6,并在用 PMA 刺激后产生较低水平的 ROS。总之,我们的结果表明 Fbln7-C 可以与中性粒细胞表面的整合素 β1 结合并调节其炎症功能。Fbln7-C(10 μg/剂量)的给药显着提高了存活率并减少了嗜中性粒细胞对炎症部位的浸润。此外,与未治疗的对照相比,浸润到 Fbln7-C 给药动物发炎腹膜中的中性粒细胞表达较低水平的 CD11b 标记物 IL-6,并在用 PMA 刺激后产生较低水平的 ROS。总之,我们的结果表明 Fbln7-C 可以与中性粒细胞表面的整合素 β1 结合并调节其炎症功能。Fbln7-C(10 μg/剂量)的给药显着提高了存活率并减少了嗜中性粒细胞对炎症部位的浸润。此外,与未治疗的对照相比,浸润到 Fbln7-C 给药动物发炎腹膜中的中性粒细胞表达较低水平的 CD11b 标记物 IL-6,并在用 PMA 刺激后产生较低水平的 ROS。总之,我们的结果表明 Fbln7-C 可以与中性粒细胞表面的整合素 β1 结合并调节其炎症功能。
更新日期:2020-07-01
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