ARAP3 protects from excessive formylated peptide-induced microvascular leakage by acting on endothelial cells and neutrophils

Vascular permeability is temporarily heightened during inflammation, but excessive inflammation-associated microvascular leakage can be detrimental, as evidenced in the inflamed lung. Formylated peptides regulate vascular leakage indirectly via formylated peptide receptor-1 (FPR1)-mediated recruitment and activation of neutrophils. Here we identify how the GTPase-activating protein ARAP3 protects against formylated peptide-induced microvascular permeability via endothelial cells and neutrophils. In vitro, Arap3−/− endothelial monolayers were characterised by enhanced formylated peptide-induced permeability due to upregulated endothelial FPR1 and enhanced vascular endothelial cadherin internalisation. In vivo, enhanced inflammation-associated microvascular leakage was observed in Arap3−/− mice. Leakage of plasma protein into the lungs of Arap3−/− mice increased within hours of formylated peptide administration. Adoptive transfer experiments indicated this was dependent upon ARAP3 deficiency in both immune and non-immune cells. Bronchoalveolar lavages of formylated peptide-challenged Arap3−/− mice contained neutrophil extracellular traps (NETs). Pharmacological inhibition of NET formation abrogated excessive microvascular leakage, indicating a critical function of NETs in this context. The observation that Arap3−/− mice developed more severe influenza suggests these findings are pertinent to pathological situations characterised by abundant formylated peptides.</p

Leadership and Expectation: Thomas Pynchon

[Extract] 'What can I do? There is absolutely nothing I can change.' This kind of statement will be familiar to anyone who has worked in a complex organisation. It denotes a vague feeling of helplessness brought on by one's perceived inability to influence the organisation or pursue meaningful courses of action in the face of its anonymous 'hierarchy' and powerful bosses. However, the statement takes on a different order of salience and implication when uttered by a top manager. In a concrete case known to one of the authors, this erie de cour came from a director of what was, at the time, the second largest bank in Germany. The author was, himself, a member of the second tier of management and responsible to the executive board. Together with one colleague he was responsible for the complete back-office activities concerning transactions for securities, custody and payments. These departments had a combined workforce of about 3000 employees