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

Proceedings of the National Academy of Sciences of the United States of America 2024 May 07

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Eosinophil recruitment is a pathological hallmark of many allergic and helminthic diseases. Here, we investigated chemokine receptor CCR3-induced 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 CCR3-induced eosinophil recruitment in vivo rendering this enzyme an attractive target in reducing unwanted eosinophil infiltration in various disorders including allergic diseases.

Citation

Roland Immler, Katrin Nussbaumer, Axel Doerner, Omar El Bounkari, Silke Huber, Janine Abisch, Matteo Napoli, Sarah Schmidt, Andreas Margraf, Monika Pruenster, Ina Rohwedder, Baerbel Lange-Sperandio, Marcus A Mall, Renske de Jong, Caspar Ohnmacht, Juergen Bernhagen, David Voehringer, Jamey D Marth, David Frommhold, Markus Sperandio. CCR3-dependent eosinophil recruitment is regulated by sialyltransferase ST3Gal-IV. Proceedings of the National Academy of Sciences of the United States of America. 2024 May 07;121(19):e2319057121