title: Human IgA Fc receptor FcαRI (CD89) triggers different forms of neutrophil death depending on the inflammatory microenvironment.
abstract: FcαRI (CD89), the human Fc receptor for IgA, is highly expressed on neutrophil granulocytes. In this study, we show that FcαRI induces different forms of neutrophil death, depending on the inflammatory microenvironment. The susceptibility of inflammatory neutrophils from sepsis or rheumatoid arthritis toward death induced by specific mAb, or soluble IgA at high concentrations, was enhanced. Although unstimulated cells experienced apoptosis following anti-FcαRI mAb stimulation, preactivation with cytokines or TLR agonists in vitro enhanced FcαRI-mediated death by additional recruitment of caspase-independent pathways, but this required PI3K class IA and MAPK signaling. Transmission electron microscopy of FcαRI-stimulated cells revealed cytoplasmic changes with vacuolization and mitochondrial swelling, nuclear condensation, and sustained plasma membrane. Coculture experiments with macrophages revealed anti-inflammatory effects of the partially caspase-independent death of primed cells following FcαRI engagement. Our data suggest that FcαRI has the ability to regulate neutrophil viability and to induce different forms of neutrophils depending on the inflammatory microenvironment and specific characteristics of the ligand-receptor interactions. Furthermore, these findings have potential implications for FcαRI-targeted strategies to treat neutrophil-associated inflammatory diseases.
authors.affiliation: Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland;
authors.forename: Marc
authors.initials: M
authors.lastname: Wehrli
authors.affiliation: Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland;
authors.forename: Fabiola
authors.initials: F
authors.lastname: Cortinas-Elizondo
authors.affiliation: Institute of Anatomy, University of Bern, CH-3012 Bern, Switzerland;
authors.forename: Ruslan
authors.initials: R
authors.lastname: Hlushchuk
authors.affiliation: Intensive Care Unit, Spital Netz Bern, CH-3004 Bern, Switzerland;
authors.forename: Fritz
authors.initials: F
authors.lastname: Daudel
authors.affiliation: Department of Rheumatology, Clinical Immunology, and Allergology, University Hospital Bern, CH-3010 Bern, Switzerland; and.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Villiger
authors.affiliation: Research and Development, CSL Behring, CH-3014 Bern, Switzerland.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Miescher
authors.affiliation: Research and Development, CSL Behring, CH-3014 Bern, Switzerland.
authors.forename: Adrian W
authors.initials: AW
authors.lastname: Zuercher
authors.affiliation: Institute of Anatomy, University of Bern, CH-3012 Bern, Switzerland;
authors.forename: Valentin
authors.initials: V
authors.lastname: Djonov
authors.affiliation: Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland;
authors.forename: Hans-Uwe
authors.initials: HU
authors.lastname: Simon
authors.affiliation: Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland; stephan.vongunten@pki.unibe.ch.
authors.forename: Stephan
authors.initials: S
authors.lastname: von Gunten
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011961:Receptors, Fc / Q000276:immunology / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000819:agonists
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016207:Cytokines; C036832:Fc(alpha) receptor; D018836:Inflammation Mediators; D011961:Receptors, Fc; D051193:Toll-Like Receptors; D019869:Phosphatidylinositol 3-Kinases