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Platelets have been implicated in the pathogenesis of ALI\/ARDS, but the underlying mechanisms are not fully understood. Here, we show that the immunoreceptor tyrosine-based activation motif\u2013coupled immunoglobulin-like platelet receptor, glycoprotein VI (GPVI), plays a key role in the early phase of pulmonary thrombo-inflammation in a model of lipopolysaccharide (LPS)-induced ALI in mice. In wild-type (WT) control mice, intranasal LPS application triggered severe pulmonary and blood neutrophilia, hypothermia, and increased blood lactate levels. In contrast, GPVI-deficient mice as well as anti-GPVI\u2013treated WT mice were markedly protected from pulmonary and systemic compromises and showed no increased pulmonary bleeding. High-resolution multicolor microscopy of lung sections and intravital confocal microcopy of the ventilated lung revealed that anti-GPVI treatment resulted in less stable platelet interactions with neutrophils and overall reduced platelet\u2013neutrophil complex (PNC) formation. Anti-GPVI treatment also reduced neutrophil crawling and adhesion on endothelial cells, resulting in reduced neutrophil transmigration and alveolar infiltrates. Remarkably, neutrophil activation was also diminished in anti-GPVI\u2013treated animals, associated with strongly reduced formation of PNC clusters and neutrophil extracellular traps (NETs) compared with that in control mice. These results establish GPVI as a key mediator of neutrophil recruitment, PNC formation, and NET formation (ie, NETosis) in experimental ALI. Thus, GPVI inhibition might be a promising strategy to reduce the acute pulmonary inflammation that causes ALI\/ARDS.<\/jats:p>","DOI":"10.1182\/blood.2023019940","type":"journal-article","created":{"date-parts":[[2023,7,13]],"date-time":"2023-07-13T17:57:47Z","timestamp":1689271067000},"page":"1463-1477","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":107,"title":["A key role for platelet GPVI in neutrophil recruitment, migration, and NETosis in the early stages of acute lung injury"],"prefix":"10.1182","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9748-7967","authenticated-orcid":false,"given":"Philipp","family":"Burkard","sequence":"first","affiliation":[{"name":"1Institute of Experimental Biomedicine, Chair of Experimental Biomedicine I, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"},{"name":"2Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Schonhart","sequence":"additional","affiliation":[{"name":"1Institute of Experimental Biomedicine, Chair of Experimental Biomedicine I, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9400-4701","authenticated-orcid":false,"given":"Timo","family":"V\u00f6gtle","sequence":"additional","affiliation":[{"name":"1Institute of Experimental Biomedicine, Chair of Experimental Biomedicine I, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"},{"name":"2Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"K\u00f6hler","sequence":"additional","affiliation":[{"name":"3Department of Anesthesiology and Intensive Care Medicine, University Hospital, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3427-1573","authenticated-orcid":false,"given":"Linyan","family":"Tang","sequence":"additional","affiliation":[{"name":"3Department of Anesthesiology and Intensive Care Medicine, University Hospital, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Johnson","sequence":"additional","affiliation":[{"name":"1Institute of Experimental Biomedicine, Chair of Experimental Biomedicine I, University Hospital W\u00fcrzburg, W\u00fcrzburg, Germany"},{"name":"2Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1852-6513","authenticated-orcid":false,"given":"Katherina","family":"Hemmen","sequence":"additional","affiliation":[{"name":"2Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2372-6800","authenticated-orcid":false,"given":"Katrin G.","family":"Heinze","sequence":"additional","affiliation":[{"name":"2Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universit\u00e4t W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Zarbock","sequence":"additional","affiliation":[{"name":"4Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital M\u00fcnster, M\u00fcnster, 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