Frontline Science: Pathological conditioning of human neutrophils recruited to the airway milieu in cystic fibrosis

Osric A Forrest; Sarah A Ingersoll; Marcela K Preininger; Julie Laval; Dominique H Limoli; Milton R Brown; Frances E Lee; Brahmchetna Bedi; Ruxana T Sadikot; Joanna B Goldberg; Vin Tangpricha; Amit Gaggar; Rabindra Tirouvanziam

doi:10.1002/JLB.5HI1117-454RR

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Frontline Science: Pathological conditioning of human neutrophils recruited to the airway milieu in cystic fibrosis

Journal article

Peer reviewed

Frontline Science: Pathological conditioning of human neutrophils recruited to the airway milieu in cystic fibrosis

Osric A Forrest, Sarah A Ingersoll, Marcela K Preininger, Julie Laval, Dominique H Limoli, Milton R Brown, Frances E Lee, Brahmchetna Bedi, Ruxana T Sadikot, Joanna B Goldberg, …

Journal of leukocyte biology, Vol.104(4), pp.665-675

10/2018

DOI: 10.1002/JLB.5HI1117-454RR

PMCID: PMC6956843

PMID: 29741792

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https://www.ncbi.nlm.nih.gov/pmc/articles/6956843View

Open Access

Abstract

Recruitment of neutrophils to the airways, and their pathological conditioning therein, drive tissue damage and coincide with the loss of lung function in patients with cystic fibrosis (CF). So far, these key processes have not been adequately recapitulated in models, hampering drug development. Here, we hypothesized that the migration of naïve blood neutrophils into CF airway fluid in vitro would induce similar functional adaptation to that observed in vivo, and provide a model to identify new therapies. We used multiple platforms (flow cytometry, bacteria-killing, and metabolic assays) to characterize functional properties of blood neutrophils recruited in a transepithelial migration model using airway milieu from CF subjects as an apical chemoattractant. Similarly to neutrophils recruited to CF airways in vivo, neutrophils migrated into CF airway milieu in vitro display depressed phagocytic receptor expression and bacterial killing, but enhanced granule release, immunoregulatory function (arginase-1 activation), and metabolic activities, including high Glut1 expression, glycolysis, and oxidant production. We also identify enhanced pinocytic activity as a novel feature of these cells. In vitro treatment with the leukotriene pathway inhibitor acebilustat reduces the number of transmigrating neutrophils, while the metabolic modulator metformin decreases metabolism and oxidant production, but fails to restore bacterial killing. Interestingly, we describe similar pathological conditioning of neutrophils in other inflammatory airway diseases. We successfully tested the hypothesis that recruitment of neutrophils into airway milieu from patients with CF in vitro induces similar pathological conditioning to that observed in vivo, opening new avenues for targeted therapeutic intervention.

Flow Cytometry

Animals

Azabicyclo Compounds - pharmacology

Benzoates - pharmacology

Blood Cells

Bone Marrow Cells

Cells, Cultured

Chemotaxis, Leukocyte

Culture Media, Conditioned - pharmacology

Cystic Fibrosis - immunology

Cystic Fibrosis - pathology

Exocytosis - drug effects

Glycolysis

Humans

Leukocyte Elastase - metabolism

Leukotriene B4 - pharmacology

Lipopolysaccharides - pharmacology

Metformin - pharmacology

Mice

Neutrophil Activation

Neutrophils - drug effects

Neutrophils - immunology

Neutrophils - metabolism

Neutrophils - pathology

Oxygen Consumption

Pinocytosis

Pseudomonas aeruginosa

Respiratory System - immunology

Respiratory System - pathology

Sputum - immunology

Transendothelial and Transepithelial Migration - drug effects

Details

Title: Subtitle: Frontline Science: Pathological conditioning of human neutrophils recruited to the airway milieu in cystic fibrosis
Creators: Osric A Forrest - Center for CF & Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
Sarah A Ingersoll - Center for CF & Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
Marcela K Preininger - Center for CF & Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
Julie Laval - Center for CF & Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
Dominique H Limoli - University of Iowa, Microbiology and Immunology
Milton R Brown - University of Iowa, Otolaryngology
Frances E Lee - Department of Medicine, Emory University, Atlanta, Georgia, USA
Brahmchetna Bedi - Atlanta VA Medical Center, Decatur, Georgia, USA
Ruxana T Sadikot - Atlanta VA Medical Center, Decatur, Georgia, USA
Joanna B Goldberg - Emory University
Vin Tangpricha - Emory University
Amit Gaggar - Birmingham VA Medical Center, Birmingham, Alabama, USA
Rabindra Tirouvanziam - Center for CF & Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
Resource Type: Journal article
Publication Details: Journal of leukocyte biology, Vol.104(4), pp.665-675
DOI: 10.1002/JLB.5HI1117-454RR
PMID: 29741792
PMCID: PMC6956843
NLM abbreviation: J Leukoc Biol
ISSN: 0741-5400
eISSN: 1938-3673
Grant note: R01 AI121252 / NIAID NIH HHS UL1 TR000454 / NCATS NIH HHS MCCART15RC / Cystic Fibrosis Foundation T32 AA013528 / NIH HHS UL1TR000454 / NIH HHS TIROUV15A0 / Cystic Fibrosis Foundation R01 HL126603 / NHLBI NIH HHS the Emory Pediatrics Startup, EECR Seed, and URC Programs R01HL126603 / NIH HHS T32 AA013528 / NIAAA NIH HHS R01HL102371 / NIH HHS TANGPR12A0 / Cystic Fibrosis Foundation TIROUV13P0 / Cystic Fibrosis Foundation R01 HL102371 / NHLBI NIH HHS
Language: English
Date published: 10/2018
Academic Unit: Microbiology and Immunology
Record Identifier: 9984210532502771

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