Alveolar epithelial and vascular CXCR2 mediates transcytosis of CXCL1 in inflamed lungs

Katharina Thomas; Jan Rossaint; Nadine Ludwig; Sina Mersmann; Niklas Kötting; Julia Grenzheuser; Lena Schemmelmann; Marina Oguama; Andreas Margraf; Helena Block; Katharina Henke; Katharina Hellenthal; Valbona Mirakaj; Volker Gerke; Uwe Hansen; Karin Gäher; Miguel Engelhardt; Johannes Roth; Johannes Eble; Elin Hub; Antal Rot; Ronen Alon; Alexander Zarbock

doi:10.1038/s41467-025-60174-w

Alveolar epithelial and vascular CXCR2 mediates transcytosis of CXCL1 in inflamed lungs

Katharina Thomas, Jan Rossaint, Nadine Ludwig, Sina Mersmann, Niklas Kötting, Julia Grenzheuser, Lena Schemmelmann, Marina Oguama, Andreas Margraf, Helena Block, Katharina Henke, Katharina Hellenthal, Valbona Mirakaj, Volker Gerke, Uwe Hansen, Karin Gäher, Miguel Engelhardt, Johannes Roth, Johannes Eble, Elin HubAntal Rot, Ronen Alon, Alexander Zarbock^*

^*Corresponding author for this work

Department of Immunology and Regenerative Biology

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	4846
Journal	Nature Communications
Volume	16
DOIs	https://doi.org/10.1038/s41467-025-60174-w
Publication status	Published Online - 24 May 2025

Funding

This work was funded by the Deutsche Forschungsgemeinschaft (DFG grant number ZA428/24-1, CO2096/2-1, ZA428/18-2, INST211/1073-1, ZA428/14-2, INST 211/984-1, INST211/604-3, TRR332 project C01 and CRC1450 project B05 to A.Z., RO 4537/4-2, RO 4537/5-2, and CRC1450 project C07 to J.R.), the IZKF Münster (Za2/001/18 to A.Z.) and GIF grant number I-1470-412.13/2018 (to R.A. and A.Z.). A.R. and E.H. were supported by the Wellcome Trust (Investigator Award 200817/Z/16/Z to A.R.).

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Thomas, K., Rossaint, J., Ludwig, N., Mersmann, S., Kötting, N., Grenzheuser, J., Schemmelmann, L., Oguama, M., Margraf, A., Block, H., Henke, K., Hellenthal, K., Mirakaj, V., Gerke, V., Hansen, U., Gäher, K., Engelhardt, M., Roth, J., Eble, J., ... Zarbock, A. (2025). Alveolar epithelial and vascular CXCR2 mediates transcytosis of CXCL1 in inflamed lungs. Nature Communications, 16, Article 4846. Advance online publication. https://doi.org/10.1038/s41467-025-60174-w

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title = "Alveolar epithelial and vascular CXCR2 mediates transcytosis of CXCL1 in inflamed lungs",

abstract = "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{\textquoteright}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.",

author = "Katharina Thomas and Jan Rossaint and Nadine Ludwig and Sina Mersmann and Niklas K{\"o}tting and Julia Grenzheuser and Lena Schemmelmann and Marina Oguama and Andreas Margraf and Helena Block and Katharina Henke and Katharina Hellenthal and Valbona Mirakaj and Volker Gerke and Uwe Hansen and Karin G{\"a}her and Miguel Engelhardt and Johannes Roth and Johannes Eble and Elin Hub and Antal Rot and Ronen Alon and Alexander Zarbock",

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doi = "10.1038/s41467-025-60174-w",

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Thomas, K, Rossaint, J, Ludwig, N, Mersmann, S, Kötting, N, Grenzheuser, J, Schemmelmann, L, Oguama, M, Margraf, A, Block, H, Henke, K, Hellenthal, K, Mirakaj, V, Gerke, V, Hansen, U, Gäher, K, Engelhardt, M, Roth, J, Eble, J, Hub, E, Rot, A, Alon, R & Zarbock, A 2025, 'Alveolar epithelial and vascular CXCR2 mediates transcytosis of CXCL1 in inflamed lungs', Nature Communications, vol. 16, 4846. https://doi.org/10.1038/s41467-025-60174-w

TY - JOUR

T1 - Alveolar epithelial and vascular CXCR2 mediates transcytosis of CXCL1 in inflamed lungs

AU - Thomas, Katharina

AU - Rossaint, Jan

AU - Ludwig, Nadine

AU - Mersmann, Sina

AU - Kötting, Niklas

AU - Grenzheuser, Julia

AU - Schemmelmann, Lena

AU - Oguama, Marina

AU - Margraf, Andreas

AU - Block, Helena

AU - Henke, Katharina

AU - Hellenthal, Katharina

AU - Mirakaj, Valbona

AU - Gerke, Volker

AU - Hansen, Uwe

AU - Gäher, Karin

AU - Engelhardt, Miguel

AU - Roth, Johannes

AU - Eble, Johannes

AU - Hub, Elin

AU - Rot, Antal

AU - Alon, Ronen

AU - Zarbock, Alexander

PY - 2025/5/24

Y1 - 2025/5/24

N2 - 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.

AB - 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.

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AN - SCOPUS:105005773762

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 4846

ER -

Alveolar epithelial and vascular CXCR2 mediates transcytosis of CXCL1 in inflamed lungs

Abstract

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