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Formylated peptides regulate vascular leakage indirectly via formylated peptide receptor\u20101 (FPR1)\u2010mediated recruitment and activation of neutrophils. Here we identify how the GTPase\u2010activating protein ARAP3 protects against formylated peptide\u2010induced microvascular permeability via endothelial cells and neutrophils. <jats:italic>In vitro<\/jats:italic>, <jats:italic>Arap3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> endothelial monolayers were characterised by enhanced formylated peptide\u2010induced permeability due to upregulated endothelial FPR1 and enhanced vascular endothelial cadherin internalisation. <jats:italic>In vivo<\/jats:italic>, enhanced inflammation\u2010associated microvascular leakage was observed in <jats:italic>Arap3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Leakage of plasma protein into the lungs of <jats:italic>Arap3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice increased within hours of formylated peptide administration. Adoptive transfer experiments indicated this was dependent upon ARAP3 deficiency in both immune and non\u2010immune cells. Bronchoalveolar lavages of formylated peptide\u2010challenged <jats:italic>Arap3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> 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 <jats:italic>Arap3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice developed more severe influenza suggests these findings are pertinent to pathological situations characterised by abundant formylated peptides. \u00a9 2024 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6288","type":"journal-article","created":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T01:10:14Z","timestamp":1715476214000},"page":"347-359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>ARAP3<\/scp> protects from excessive formylated peptide\u2010induced microvascular leakage by acting on endothelial cells and neutrophils"],"prefix":"10.1002","volume":"263","author":[{"given":"Julia Y","family":"Chu","sequence":"first","affiliation":[{"name":"Centre for Inflammation Research, Institute for Regeneration and Repair University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry","family":"McCormick","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research, Institute for Regeneration and Repair University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kruthika","family":"Sundaram","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research, Institute for Regeneration and Repair University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth","family":"Hardisty","sequence":"additional","affiliation":[{"name":"Centre for Inflammation Research, Institute for Regeneration and Repair University of Edinburgh  Edinburgh 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Research, Institute for Regeneration and Repair University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Amado\u2010Azevedo","sequence":"additional","affiliation":[{"name":"Department of Physiology, Amsterdam University Medical Center Vrije Universiteit, Amsterdam Cardiovascular Sciences  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L","family":"Hordijk","sequence":"additional","affiliation":[{"name":"Department of Physiology, Amsterdam University Medical Center Vrije Universiteit, Amsterdam Cardiovascular Sciences  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Caporali","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Sciences University of Edinburgh  Edinburgh 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