Inactivation of the tyrosine phosphatase SHP-2 drives vascular dysfunction in Sepsis

Heun, Yvonn; Pircher, Joachim; Czermak, Thomas; Bluem, Philipp; Hupel, Georg; Bohmer, Monica; Krämer, Björn F.; Pogoda, Kristin; Pfeifer, Alexander; Woernle, Markus; Ribeiro, Andrea; Hübner, Max; Kreth, Simone; Claus, Ralf A.; Weis, Sebastian; Ungelenk, Luisa; Kroetz, Florian; Pohl, Ulrich und Mannell, Hanna (2019): Inactivation of the tyrosine phosphatase SHP-2 drives vascular dysfunction in Sepsis. In: eBioMedicine, Bd. 42: S. 120-132

Abstract

Background: Sepsis, the most severe form of infection, involves endothelial dysfunction which contributes to organ failure. To improve therapeutic prospects, elucidation of molecular mechanisms underlying endothelial vascular failure is of essence. Methods: Polymicrobial contamination induced sepsis mouse model and primary endothelial cells incubated with sepsis serum were used to study SHP-2 in sepsis-induced endothelial inflammation. SHP-2 activity was assessed by dephosphorylation of pNPP, ROS production was measured by DCF oxidation and protein interactions were assessed by proximity ligation assay. Vascular inflammation was studied in the mouse cremaster model and in an in vitro flow assay. Findings: We identified ROS-dependent inactivation of the tyrosine phosphatase SHP-2 to be decisive for endothelial activation in sepsis. Using in vivo and in vitro sepsis models, we observed a significant reduction of endothelial SHP-2 activity, accompanied by enhanced adhesion molecule expression. The impaired SHP-2 activitywas restored by ROS inhibitors and an IL-1 receptor antagonist. SHP-2 activity inversely correlatedwith the adhesive phenotype of endothelial cells exposed to IL-1 beta as well as sepsis serum via p38 MAPK and NF-kappa B. In vivo, SHP-2 inhibition accelerated IL-1 beta-induced leukocyte adhesion, extravasation and vascular permeability. Mechanistically, SHP-2 directly interacts with the IL-1R1 adaptor protein MyD88 via its tyrosine 257, resulting in reduced binding of p85/PI3-K to MyD88. Interpretation: Our data show that SHP-2 inactivation by ROS in sepsis releases a protective break, resulting in endothelial activation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2352-3964
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198