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

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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.