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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Artículo Open Access |
| Published: |
Wiley
2024
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| Subjects: | |
| Online Access: | https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6288 |
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Table of Contents:
- ARAP3 protects from excessive formylated peptide‐induced microvascular leakage by acting on endothelial cells and neutrophils Julia Y Chu Barry McCormick Kruthika Sundaram Gareth Hardisty Utsa Karmakar Caroline Pumpe Elizabeth Krull Christopher D Lucas Joana Amado‐Azevedo Peter L Hordijk Andrea Caporali Harry Mellor J Kenneth Baillie Adriano G Rossi Sonja Vermeren The Journal of Pathology AbstractVascular 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. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. 10.1002/path.6288 http://creativecommons.org/licenses/by/4.0/