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Fibrin is a critical regulator of neutrophil effector function at mucosal barrier sites
bioRxiv - Immunology Pub Date : 2021-01-17 , DOI: 10.1101/2021.01.15.426743
Lakmali M Silva , Andrew D Doyle , Collin L Tran , Teresa Greenwell-Wild , Nicolas Dutzan , Andrew G Lum , Cary S Agler , Megan Sibree , Priyam Jani , Daniel Martin , Vardit Kram , Francis J Castellino , Matthew J Flick , Kimon Divaris , Thomas H Bugge , Niki M Moutsopoulos

Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we document that the clotting factor fibrin is a critical regulator of neutrophil function at mucosal barriers. We demonstrate that fibrin engages neutrophils through the aMb2 integrin receptor and activates effector functions, including the production of reactive oxygen species and NET formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis. Indeed, the accumulation of fibrin due to Mendelian genetic defects in plasmin leads to severe oral mucosal immunopathology in mice and humans. Concordantly, genetic polymorphisms in the human PLG gene, encoding plasminogen, are associated with common forms of the oral mucosal disease periodontitis. Our work uncovers fibrin as a critical regulator of neutrophil effector function within the mucosal tissue microenvironment and suggests fibrin-neutrophil engagement as a pathogenic instigator and therapeutic target in common mucosal disease.

中文翻译:

纤维蛋白是黏膜屏障位点中性粒细胞效应子功能的关键调节剂

组织特异性提示对于粘膜屏障的动态平衡至关重要。在这里,我们证明凝血因子纤维蛋白是黏膜屏障中嗜中性粒细胞功能的关键调节剂。我们证明血纤蛋白通过aMb2整合素受体参与嗜中性粒细胞并激活效应器功能,包括活性氧的产生和NET的形成。在纤溶酶介导的纤维蛋白溶解受损的情况下,这些免疫保护性中性粒细胞功能会损害组织。实际上,由于纤溶酶中孟德尔遗传缺陷所致的纤维蛋白积聚导致小鼠和人类严重的口腔粘膜免疫病理。相应地,编码纤溶酶原的人PLG基因的遗传多态性与口腔粘膜疾病牙周炎的常见形式有关。
更新日期:2021-01-18
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