Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 146, Issue 2, Pages 377-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2020.01.013
Keywords
Eosinophils; galectins; Charcot-Leyden; ribonucleases; EDN; ECP; RNase 2; RNase 3; granulogenesis
Categories
Funding
- National Institutes of Health (NIH) [AI025230]
- NIH [T32 DK07739]
- NIH National Research Service Award Fellowship [F32 AI51137]
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Background: The human eosinophil Charcot-Leyden crystal (CLC) protein is a member of the Galectin superfamily and is also known as galectin-10 (Gal-10). CLC/Gal-10 forms the distinctive hexagonal bipyramidal crystals that are considered hallmarks of eosinophil participation in allergic responses and related inflammatory reactions; however, the glycan-containing ligands of CLC/Gal-10, its cellular function(s), and its role(s) in allergic diseases are unknown. Objective: We sought to determine the binding partners of CLC/Gal-10 and elucidate its role in eosinophil biology. Methods: Intracellular binding partners were determined by ligand blotting with CLC/Gal-10, followed by coimmunoprecipitation and coaffinity purifications. The role of CLC/Gal-10 in eosinophil function was determined by using enzyme activity assays, confocal microscopy, and short hairpin RNA knockout of CLC/Gal-10 expression in human CD34(+) cord blood hematopoietic progenitors differentiated to eosinophils. Results: CLC/Gal-10 interacts with both human eosinophil granule cationic ribonucleases (RNases), namely, eosinophil-derived neurotoxin (RNS2) and eosinophil cationic protein (RNS3), and with murine eosinophil-associated RNases. The interaction is independent of glycosylation and is not inhibitory toward endoRNase activity. Activation of eosinophils with INF-gamma induces the rapid colocalization of CLC/Gal-10 with eosinophil-derived neurotoxin/RNS2 and CD63. Short hairpin RNA knockdown of CLC/Gal-10 in human cord blood derived CD34+ progenitor cells impairs eosinophil granulogenesis. Conclusions: CLC/Gal-10 functions as a carrier for the sequestration and vesicular transport of the potent eosinophil granule cationic RNases during both differentiation and degranulation, enabling their intracellular packaging and extracellular functions in allergic inflammation.
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