The role of protein tyrosine phosphatases for the regulation of integrin activity and leukocyte recruitment.
Final Report Abstract
Leukocyte recruitment to the site of inflammation plays a pivotal role in host defence. During the last years, many studies investigating the activating molecular mechanisms resulting in leukocyte recruitment, were performed. However, to prevent excessive inflammatory processes and tissue destruction, as well as to understand the molecular mechanisms of autoimmune diseases, processes regulating leukocyte deactivation have to be investigated. Neutrophil adhesion in acute inflammation is mediated by activation of the β2-integrins LFA-1 and Mac-1. Despite the clinical importance, cell intrinsic molecular mechanism of negative regulation of integrin in adhesiveness and neutrophil recruitment are poorly understood. In this study we used different knock out mouse models to determine the impact of different molecules that negatively regulate leukocyte recruitment. For this purpose, we analysed 3 different phosphatases, one kinase and one ITIM containing receptor known to play a role as a SFK negative regulators. Loss of function of each of the molecules resulted in severe phenotypes influencing different steps of the leukocyte recruitment cascade. We demonstrated that the phosphatases SHP-1, CD45 and CD148 as well as the kinase Csk and the ITIM Ly49Q are key molecules for integrin activity regulation on neutrophils during leukocyte recruitment. Neutrophil effector functions like ROS production and phagocytosis are also dependent on the investigated molecules. By demonstrating the effects of loss of functions of these molecules in different murine inflammatory disease models, we clearly showed the importance of SHP-1, CD45, CD148, Ly49Q and Csk within the regulation of inflammatory processes.
Publications
- 2013. Integrin Regulation during Leukocyte Recruitment. J Immunol 190:4451-4457
Herter J, Zarbock A
(See online at https://doi.org/10.4049/jimmunol.1203179) - 2014. Leukocyte extravasation and vascular permeability are each controlled in vivo by different tyrosine residues of VE-cadherin. Nat Immunol 15:223-230
Wessel F, Winderlich M, Holm M, Frye M, Rivera-Galdos R, Vockel M, Linnepe R, Ipe U, Stadtmann A, Zarbock A, Nottebaum AF, Vestweber D
(See online at https://doi.org/10.1038/ni.2824) - 2015. Cross-Talk between Shp1 and PIPKIgamma Controls Leukocyte Recruitment. J Immunol 195:1152-1161
Stadtmann, A., H. Block, S. Volmering, C. Abram, C. Sohlbach, M. Boras, C.A. Lowell, and A. Zarbock
(See online at https://doi.org/10.4049/jimmunol.1500606) - 2015. Mutation in the CD45 inhibitory wedge modulates integrin activation and leukocyte recruitment during inflammation. J Immunol 194:728-738
Germena, G., S. Volmering, C. Sohlbach, and A. Zarbock
(See online at https://doi.org/10.4049/jimmunol.1401646) - 2018. The ITIM Domain-Containing NK Receptor Ly49Q Impacts Pulmonary Infection by Mediating Neutrophil Functions. J Immunol 200:4085-4093
Margraf, A., S. Volmering, J. Skupski, V. Van Marck, A.P. Makrigiannis, H. Block, and A. Zarbock
(See online at https://doi.org/10.4049/jimmunol.1701084)
