Neutrophil azurophilic granule exocytosis is primed by TNF-α and partially regulated by NADPH oxidase

Renee M. Potera, Melissa J. Jensen, Brieanna M. Hilkin, Gina K. South, Jessica S. Hook, Emily A. Gross, Jessica G. Moreland

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Neutrophil (polymorphonuclear leukocyte) activation with release of granule contents plays an important role in the pathogenesis of acute lung injury, prompting clinical trials of inhibitors of neutrophil elastase. Despite mounting evidence for neutrophil-mediated host tissue damage in a variety of disease processes, mechanisms regulating azurophilic granule exocytosis at the plasma membrane, and thus release of elastase and other proteases, are poorly characterized. We hypothesized that azurophilic granule exocytosis would be enhanced under priming conditions similar to those seen during acute inflammatory events and during chronic inflammatory disease, and selected the cytokine TNF-α to model this in vitro. Neutrophils stimulated with TNF-α alone elicited intracellular reactive oxygen species (ROS) generation and mobilization of secretory vesicles, specific, and gelatinase granules. p38 and ERK1/2 MAPK were involved in these components of priming. TNF-α priming alone did not mobilize azurophilic granules to the cell surface, but did markedly increase elastase release into the extracellular space in response to secondary stimulation with N-formyl-Met-Leu-Phe (fMLF). Priming of fMLF-stimulated elastase release was further augmented in the absence of NADPH oxidase-derived ROS. Our findings provide a mechanism for host tissue damage during neutrophil-mediated inflammation and suggest a novel anti-inflammatory role for the NADPH oxidase.

Original languageEnglish (US)
Pages (from-to)635-646
Number of pages12
JournalInnate Immunity
Volume22
Issue number8
DOIs
StatePublished - Nov 1 2016

Fingerprint

NADPH Oxidase
Exocytosis
Neutrophils
Pancreatic Elastase
Reactive Oxygen Species
Secretory Proteinase Inhibitory Proteins
Gelatinases
Acute Lung Injury
Secretory Vesicles
Extracellular Space
Peptide Hydrolases
Chronic Disease
Anti-Inflammatory Agents
Cell Membrane
Clinical Trials
Cytokines
Inflammation

Keywords

  • Elastase
  • inflammation
  • NADPH oxidase 2
  • priming
  • reactive oxygen species
  • signaling

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Molecular Biology
  • Cell Biology
  • Infectious Diseases

Cite this

Neutrophil azurophilic granule exocytosis is primed by TNF-α and partially regulated by NADPH oxidase. / Potera, Renee M.; Jensen, Melissa J.; Hilkin, Brieanna M.; South, Gina K.; Hook, Jessica S.; Gross, Emily A.; Moreland, Jessica G.

In: Innate Immunity, Vol. 22, No. 8, 01.11.2016, p. 635-646.

Research output: Contribution to journalArticle

Potera, Renee M. ; Jensen, Melissa J. ; Hilkin, Brieanna M. ; South, Gina K. ; Hook, Jessica S. ; Gross, Emily A. ; Moreland, Jessica G. / Neutrophil azurophilic granule exocytosis is primed by TNF-α and partially regulated by NADPH oxidase. In: Innate Immunity. 2016 ; Vol. 22, No. 8. pp. 635-646.
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