The mammalian sterile 20-like kinase 1 (MST1) is a critical regulator of neutrophil transmigration during inflammation

炎症过程中白细胞的募集是一个重要的免疫学过程，使白细胞能够离开血管内室并迁移到炎症组织中。白细胞的募集遵循一系列粘附和活化事件，其可大致分为白细胞滚动、白细胞粘附和白细胞移行。一些人描述了先天性免疫缺陷疾病（例如白细胞粘附缺陷I，LAD-I）导致白细胞募集的强烈减少，有利于严重细菌感染的发展。2012年，三个独立的研究小组（包括我们的合作伙伴Christoph Klein教授，LMU慕尼黑儿童医院）描述了一种新的免疫缺陷疾病，其特征是哺乳动物不育20样激酶1（MST 1）基因的功能缺失突变。患有这种疾病的患者表现出频繁复发的细菌和病毒感染，明显的淋巴细胞减少症和细胞凋亡增加。在相应的小鼠模型（Mst 1缺陷小鼠）中，可以显示淋巴细胞粘附的严重减少，这是由含有β 2整联蛋白LFA-1的囊泡向淋巴细胞表面的动员缺陷引起的。目前，缺乏对Mst 1缺陷型中性粒细胞（和单核细胞）粘附特性的研究。因此，我们的研究计划旨在调查MST 1缺陷中性粒细胞在适当的小鼠模型和MST 1缺陷患者的粘附功能。我们的第一个初步研究结果令人惊讶地表明，Mst 1缺陷型中性粒细胞表现出正常的LFA-1依赖的粘附在小鼠和man. However，使用活体多光子显微镜在提睾肌Mst 1缺陷型小鼠，我们可以显示出严重损害的中性粒细胞的迁移在基底膜渗透的水平。这似乎伴随着整合素VLA 3和VLA 6以及中性粒细胞弹性蛋白酶（NE）向Mst 1缺陷型中性粒细胞表面的缺陷性动员。VLA 3，VLA 6和NE被讨论为在白细胞募集过程中成功穿透基底膜的重要因素。两者合计，并根据我们的初步结果，这项研究的建议是为了证明我们的假设，MST 1是一个重要的调节中性粒细胞基底膜渗透在招聘过程中确定MST 1缺乏症作为第一个免疫缺陷疾病的人与中性粒细胞基底膜渗透缺陷。

Leukocyte recruitment during inflammation is an important immunological process enabling leukocytes to leave the intravascular compartment and migrate into inflamed tissue. Recruitment of leukocytes follows a cascade of adhesion and activation events which can roughly be divided into leukocyte rolling, leukocyte adhesion and leukocyte transmigration. Several described inborn immunodeficiency disorders (f.e. leukocyte adhesion deficiency I, LAD-I) lead to a strong reduction in leukocyte recruitment favoring the development of severe bacterial infections. In 2012, three independent groups (including our collaboration partner Prof. Christoph Klein, Children s Hospital LMU Munich) described a new immunodeficiency disorder characterized by a loss-of-function mutation in the mammalian sterile 20-like kinase1 (MST1) gene. Patients with this disorder exhibit frequent recurrent bacterial and viral infections, a pronounced lymphocytopenia, and increased cell apoptosis. In the respective mouse model (Mst1-deficient mice) a severe reduction in lymphocyte adhesion could be shown which is caused by defective mobilization of beta2 integrin LFA-1 containing vesicles to the lymphocyte surface. Currently, studies on adhesion properties of Mst1-deficienct neutrophils (and monocytes) are lacking. Therefore, our research proposal aims to investigate adhesive functions of Mst1-deficient neutrophils in appropriate mouse models and in patients with MST1 deficiency. Our first preliminary results surprisingly show that Mst1-deficient neutrophils exhibit normal LFA-1 dependent adhesion in mouse and man. However, using intravital multiphoton microscopy in cremaster muscles of Mst1-deficient mice, we could show a severe impairment of neutrophil transmigration at the level of basement membrane penetration. This seems to be accompanied by defective mobilization of the integrins VLA3 and VLA6, as well as of neutrophil elastase (NE) to the surface of Mst1-deficient neutrophils. VLA3, VLA6, and NE are discussed as important factors for the successful penetration of the basement membrane during leukocyte recruitment. Taken together and based on our preliminary results, this research proposal is intended to proof our hypothesis that MST1 is a critical regulator of neutrophil basement membrane penetration during the recruitment process identifying MST1 deficiency as the first immunodeficiency disorder in man with a neutrophil basement membrane penetration defect.