Cell-type-specific regulation of acute respiratory distress syndrome by P2RY6-expressing CD11c+ cells
5 affiliations
- 1Division of Pulmonology, Department of Internal Medicine II, Comprehensive Center for Chest Diseases, Medical University of Vienna
- 2Department of Dermatology, Medical University of Vienna
- 3Department of Pathology, Medical University of Vienna
- 4Molecular Oncology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center-Gynecologic Cancer Unit, Medical University of Vienna
- 5Department of Pneumology, Medical Center, University of Freiburg
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung disorder characterized by excessive neutrophilic inflammation and increased microvascular permeability. We previously demonstrated the involvement of the G q -coupled P2Y ₂ purinergic receptor (P2RY ₂ ) in ARDS pathogenesis. Here, we investigated the contribution of the related purinergic receptor P2Y ₆ (P2RY ₆ ) and defined its cell-type-specific functions using a preclinical mouse model of ARDS. Wild-type female mice were treated with the selective P2RY ₆ antagonist MRS2578 through intratracheal administration using prophylactic and therapeutic approaches, followed by lipopolysaccharide (LPS) challenge. The role of P2RY ₆ was further evaluated in global P2ry ₆ -deficient mice and conditional knockout models targeting specific cellular compartments. Bronchoalveolar lavage (BAL) samples were analyzed by flow cytometry and multiplex cytokine assays, and lung tissues were assessed by histological and immunohistochemical analyses. Pharmacological inhibition of P2RY ₆ significantly reduced Ly6G ⁺ F4/80⁻ neutrophil accumulation, vascular leakage and pro-inflammatory cytokine and chemokine production in the ARDS model. Consistently, P2ry ₆ -deficient mice exhibited reduced Ly6G ⁺ F4/80⁻ neutrophil recruitment and attenuated inflammatory responses following LPS challenge. Cell-type-specific deletion revealed that P2RY ₆ deficiency in Vav-expressing hematopoietic cells and CD11c-expressing cells reproduced the protective phenotype observed in global P2ry ₆ knockout mice. In contrast, P2RY ₆ deletion in CD4 ⁺ T cells, Scgb1a1 -expressing airway epithelial cells or LysM-expressing myeloid cells did not significantly alter ARDS-associated inflammation. Collectively, our findings identify CD11c-expressing P2RY ₆ ⁺ cells as critical regulators of ARDS pathogenesis and highlight P2RY ₆ as a potential therapeutic target for controlling inflammatory lung injury.
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BibTeX
@article{kargarpour2026celltypespecific,
title = {{Cell-type-specific regulation of acute respiratory distress syndrome by P2RY6-expressing CD11c+ cells}},
author = {Zahra Kargarpour and Bertram Aschenbrenner and Markus Kramer and Seda Metekol and Amra Begunic and Silvana Geleff and Eva Obermayr and Robert Zeillinger and Anastasia Papaporfyriou and Andreas Renner and Beate Lichtenberger and Daniela Gompelmann and Marco Idzko and Ahmed El-Gazzar},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1940896},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1940896/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cell-type-specific regulation of acute respiratory distress syndrome by P2RY6-expressing CD11c+ cells
AU - Zahra Kargarpour
AU - Bertram Aschenbrenner
AU - Markus Kramer
AU - Seda Metekol
AU - Amra Begunic
AU - Silvana Geleff
AU - Eva Obermayr
AU - Robert Zeillinger
AU - Anastasia Papaporfyriou
AU - Andreas Renner
AU - Beate Lichtenberger
AU - Daniela Gompelmann
AU - Marco Idzko
AU - Ahmed El-Gazzar
PY - 2026
DA - 2026/10/26
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1940896
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1940896/full
AB - Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung disorder characterized by excessive neutrophilic inflammation and increased microvascular permeability. We previously demonstrated the involvement of the G q -coupled P2Y ₂ purinergic receptor (P2RY ₂ ) in ARDS pathogenesis. Here, we investigated the contribution of the related purinergic receptor P2Y ₆ (P2RY ₆ ) and defined its cell-type-specific functions using a preclinical mouse model of ARDS. Wild-type female mice were treated with the selective P2RY ₆ antagonist MRS2578 through intratracheal administration using prophylactic and therapeutic approaches, followed by lipopolysaccharide (LPS) challenge. The role of P2RY ₆ was further evaluated in global P2ry ₆ -deficient mice and conditional knockout models targeting specific cellular compartments. Bronchoalveolar lavage (BAL) samples were analyzed by flow cytometry and multiplex cytokine assays, and lung tissues were assessed by histological and immunohistochemical analyses. Pharmacological inhibition of P2RY ₆ significantly reduced Ly6G ⁺ F4/80⁻ neutrophil accumulation, vascular leakage and pro-inflammatory cytokine and chemokine production in the ARDS model. Consistently, P2ry ₆ -deficient mice exhibited reduced Ly6G ⁺ F4/80⁻ neutrophil recruitment and attenuated inflammatory responses following LPS challenge. Cell-type-specific deletion revealed that P2RY ₆ deficiency in Vav-expressing hematopoietic cells and CD11c-expressing cells reproduced the protective phenotype observed in global P2ry ₆ knockout mice. In contrast, P2RY ₆ deletion in CD4 ⁺ T cells, Scgb1a1 -expressing airway epithelial cells or LysM-expressing myeloid cells did not significantly alter ARDS-associated inflammation. Collectively, our findings identify CD11c-expressing P2RY ₆ ⁺ cells as critical regulators of ARDS pathogenesis and highlight P2RY ₆ as a potential therapeutic target for controlling inflammatory lung injury.
SN - 1664-3224
ER -