CCR3-dependent eosinophil recruitment is regulated by sialyltransferase ST3Gal-IV

• 成果类型: Article
• 署名作者: Immler, Roland; Nussbaumer, Katrin; Doerner, Axel; El Bounkari, Omar; Huber, Silke; Abisch, Janine; Napoli, Matteo; Schmidt, Sarah; Margraf, Andreas; Pruenster, Monika; Rohwedder, Ina; Lange-Sperandio, Baerbel; Mall, Marcus A.; de Jong, Renske; Ohnmacht, Caspar; Bernhagen, Juergen; Voehringer, David; Marth, Jamey D.; Frommhold, David; Sperandio, Markus
• 署名单位: University of Munich; Ruprecht Karls University Heidelberg; University of Munich; University of Munich; University of Munich; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Technical University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Munich; Munich Heart Alliance; University of Erlangen Nuremberg; Sanford Burnham Prebys Medical Discovery Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10927
• DOI: 10.1073/pnas.2319057121
• 发表日期: 2024-05-07
• 关键词: p-selectin; siglec-f; leukocyte recruitment; endothelial-cells; inflammation; eotaxin; TRAFFICKING; roles; vivo; accumulation

摘要

Eosinophil recruitment is a pathological hallmark of many allergic and helminthic diseases. Here, we investigated chemokine receptor CCR3induced eosinophil recruitment in sialyltransferase St3gal4 -/- mice. We found a marked decrease in eosinophil extravasation into CCL11 - stimulated cremaster muscles and into the inflamed peritoneal cavity of St3gal4 -/- mice. Ex vivo flow chamber assays uncovered reduced adhesion of St3gal4 -/- compared to wild type eosinophils. Using flow cytometry, we show reduced binding of CCL11 to St3gal4 -/- eosinophils. Further, we noted reduced binding of CCL11 to its chemokine receptor CCR3 isolated from St3gal4 -/- eosinophils. This was accompanied by almost absent CCR3 internalization of CCL11 - stimulated St3gal4 -/- eosinophils. Applying an ovalbumin - induced allergic airway disease model, we found a dramatic reduction in eosinophil numbers in bronchoalveolar lavage fluid following intratracheal challenge with ovalbumin in St3gal4 - deficient mice. Finally, we also investigated tissue - resident eosinophils under homeostatic conditions and found reduced resident eosinophil numbers in the thymus and adipose tissue in the absence of ST3Gal - IV. Taken together, our results demonstrate an important role of ST3Gal - IV in CCR3induced eosinophil recruitment in vivo rendering this enzyme an attractive target in reducing unwanted eosinophil infiltration in various disorders including allergic diseases. Significance Eosinophils play a major role in allergic and helminthic diseases. Recruitment of eosinophils into the inflamed tissue is regulated by eosinophil chemokine receptor CCR3 interacting with the chemokine CCL11. Our work provides evidence that sialylation of CCR3 by the sialyltransferase ST3Gal- IV is crucial for CCR3binding to CCL11 and hence critical for eosinophil trafficking under baseline and inflammatory conditions including eosinophil recruitment into the lung during allergic airway disease.