Alveolar epithelial and vascular CXCR2 mediates transcytosis of CXCL1 in inflamed lungs
Pulmonary infections are characterized by neutrophil recruitment into the lung driven by chemokine ligands of CXCR2, which is expressed on neutrophils, but also present in non-hematopoietic lung cells, in which its role remains unclear. We hypothesize that CXCR2 in epithelial and endothelial cells contributes to neutrophil recruitment into the lung by modifying the availability of its cognate chemokines in lung alveoli. Using conditional endothelial and epithelial CXCR2 knockout mice, we demonstrate that selective CXCR2 deletion in either compartment impairs neutrophil recruitment into the lung during bacterial pneumonia and reduces bacterial clearance. We show that CXCR2 ablation in epithelial and endothelial cells compromises respective trans-epithelial and trans-endothelial transcytosis of alveolar CXCL1. Mechanistically, CXCR2-mediated CXCL1 endothelial and epithelial cell transcytosis requires the function of Bruton's tyrosine kinase in these cells. In conclusion, CXCR2 plays an important role in alveolar epithelial and endothelial cells, where it mediates cognate chemokine transcytosis, thus actively supporting their activities in neutrophil recruitment to the infected lungs.
Authors
- Sina Mersmann (ORCID: https://orcid.org/0000-0001-5010-7250)
- Marina Kardell (ORCID: https://orcid.org/0000-0001-5899-5045)
- Valbona Mirakaj (ORCID: https://orcid.org/0000-0002-6907-6455)
- Julia Chiara Grenzheuser
- Andreas Margraf (ORCID: https://orcid.org/0000-0002-6539-6478)
- R. Alon (ORCID: https://orcid.org/0000-0001-9161-6369)
- Volker Gerke (ORCID: https://orcid.org/0000-0001-7208-8206)
- Alexander Zarbock (ORCID: https://orcid.org/0000-0002-2124-1714)
- Johannes A. Eble (ORCID: https://orcid.org/0000-0001-9156-2137)
- Antal Rot (ORCID: https://orcid.org/0000-0002-9730-6166)
- Niklas Martin Kötting
- Lena Schemmelmann
- Uwe Hansen (ORCID: https://orcid.org/0000-0001-8519-8228)
- Katharina E. M. Hellenthal (ORCID: https://orcid.org/0000-0002-5366-9627)
- Johannes Roth (ORCID: https://orcid.org/0000-0001-7035-8348)
- Nadine Ludwig (ORCID: https://orcid.org/0000-0001-5910-1277)
- Mélanie Engelhardt
- Katharina Henke (ORCID: https://orcid.org/0000-0003-3211-2675)
- Katharina Thomas (ORCID: https://orcid.org/0000-0002-9474-9180)
- Karin Gäher
- Jan Rossaint (ORCID: https://orcid.org/0000-0001-5524-6997)
- Elin Hub
- Helena Block
Institutions
- Queen Mary University of London (GB)
- University of Münster (DE)
- University Hospital Münster (DE)
- William Harvey Research Institute (GB)
- Weizmann Institute of Science (IL)
- University of Tübingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-24
- DOI
- https://doi.org/10.1038/s41467-025-60174-w
- Citations
- 7
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 5.58
Funders
- Wellcome
- Deutsche Forschungsgemeinschaft
- German-Israeli Foundation for Scientific Research and Development