title: Mouse and human eosinophils degranulate in response to platelet-activating factor (PAF) and lysoPAF via a PAF-receptor-independent mechanism: evidence for a novel receptor.
abstract: Platelet-activating factor (PAF [1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine]) is a phospholipid mediator released from activated macrophages, mast cells, and basophils that promotes pathophysiologic inflammation. Eosinophil responses to PAF are complex and incompletely elucidated. We show in this article that PAF and its 2-deacetylated metabolite (lysoPAF) promote degranulation (release of eosinophil peroxidase) via a mechanism that is independent of the characterized PAFR. Specifically, we demonstrate that receptor antagonists CV-3988 and WEB-2086 and pertussis toxin have no impact on PAF- or lysoPAF-mediated degranulation. Furthermore, cultured mouse eosinophils from PAFR(-/-) bone marrow progenitors degranulate in response to PAF and lysoPAF in a manner indistinguishable from their wild-type counterparts. In addition to PAF and lysoPAF, human eosinophils degranulate in response to lysophosphatidylcholine, but not phosphatidylcholine, lysophosphatidylethanolamine, or phosphatidylethanolamine, demonstrating selective responses to phospholipids with a choline head-group and minimal substitution at the sn-2 hydroxyl. Human eosinophils release preformed cytokines in response to PAF, but not lysoPAF, also via a PAFR-independent mechanism. Mouse eosinophils do not release cytokines in response to PAF or lysoPAF, but they are capable of doing so in response to IL-6. Overall, our work provides the first direct evidence for a role for PAF in activating and inducing degranulation of mouse eosinophils, a crucial feature for the interpretation of mouse models of PAF-mediated asthma and anaphylaxis. Likewise, we document and define PAF and lysoPAF-mediated activities that are not dependent on signaling via PAFR, suggesting the existence of other unexplored molecular signaling pathways mediating responses from PAF, lysoPAF, and closely related phospholipid mediators.
authors.affiliation: Section of Eosinophil Biology, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1883, USA. kdyer@niaid.nih.gov
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Dyer
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Percopo
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Xie
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yang
authors.forename: John Dongil
authors.initials: JD
authors.lastname: Kim
authors.forename: Francis
authors.initials: F
authors.lastname: Davoine
authors.forename: Paige
authors.initials: P
authors.lastname: Lacy
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
authors.forename: Redwan
authors.initials: R
authors.lastname: Moqbel
authors.forename: Helene F
authors.initials: HF
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology*; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010742:Phospholipid Ethers / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000276:immunology* / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000276:immunology* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology
chemical_list: D001381:Azepines; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; C037913:CV 3988