Fibrinogen is a specific trigger for cytolytic eosinophil degranulation

Mackenzie E. Coden, Lucas F. Loffredo, Matthew T. Walker, Brian M. Jeong, Kiwon Nam, Bruce S. Bochner, Hiam Abdala-Valencia, Sergejs Berdnikovs*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

In inflamed human tissues, we often find intact eosinophilic granules, but not eosinophils themselves. Eosinophils, tissue-dwelling granulocytes with several homeostatic roles, have a surprising association with fibrinogen and tissue remodeling. Fibrinogen is a complex glycoprotein with regulatory roles in hemostasis, tumor development, wound healing, and atherogenesis. Despite its significance, the functional link between eosinophils and fibrinogen is not understood. We tested IL-5–primed mouse bone marrow–derived and human blood–sorted eosinophil activity against FITC-linked fibrinogen substrates. The interactions between these scaffolds and adhering eosinophils were quantified using three-dimensional laser spectral, confocal, and transmission electron microscopy. Eosinophils were labeled with major basic protein (MBP) Ab to visualize granules and assessed by flow cytometry. Both mouse and human eosinophils showed firm adhesion and degraded up to 27 ± 3.1% of the substrate area. This co-occurred with active MBP-positive granule release and the expression of integrin CD11b. Mass spectrometry analysis of fibrinogen proteolytic reactions detected the presence of eosinophil peroxidase, MBP, and fibrin α-, β-, and γ-chains. Eosinophil activity was adhesion dependent, as a blocking Ab against CD11b significantly reduced adhesion, degranulation, and fibrinogenolysis. Although adhered, eosinophils exhibited no proteolytic activity on collagen matrices. Cytolytic degranulation was defined by loss of membrane integrity, cell death, and presence of cell-free granules. From transmission electron microscopy images, we observed only fibrinogen-exposed eosinophils undergoing this process. To our knowledge, this is the first report to show that fibrinogen is a specific trigger for cytolytic eosinophil degranulation with implications in human disease.

Original languageEnglish (US)
Pages (from-to)438-448
Number of pages11
JournalJournal of Immunology
Volume204
Issue number2
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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