ROS and glutathionylation balance cytoskeletal dynamics in neutrophil extracellular trap formation

Darko Stojkov; Poorya Amini; Kevin Oberson; Christiane Sokollik; Andrea Duppenthaler; Hans-Uwe Simon; Shida Yousefi

doi:10.1083/jcb.201611168

ROS and glutathionylation balance cytoskeletal dynamics in neutrophil extracellular trap formation

J Cell Biol. 2017 Dec 4;216(12):4073-4090. doi: 10.1083/jcb.201611168. Epub 2017 Nov 17.

Authors

Darko Stojkov¹, Poorya Amini¹, Kevin Oberson¹, Christiane Sokollik², Andrea Duppenthaler², Hans-Uwe Simon¹, Shida Yousefi³

Affiliations

¹ Institute of Pharmacology, University of Bern, Bern, Switzerland.
² Unit of Pediatric Infectious Diseases, University Children's Hospital Bern, Bern, Switzerland.
³ Institute of Pharmacology, University of Bern, Bern, Switzerland shida.yousefi@pki.unibe.ch.

Abstract

The antimicrobial defense activity of neutrophils partly depends on their ability to form neutrophil extracellular traps (NETs), but the underlying mechanism controlling NET formation remains unclear. We demonstrate that inhibiting cytoskeletal dynamics with pharmacological agents or by genetic manipulation prevents the degranulation of neutrophils and mitochondrial DNA release required for NET formation. Wiskott-Aldrich syndrome protein-deficient neutrophils are unable to polymerize actin and exhibit a block in both degranulation and DNA release. Similarly, neutrophils with a genetic defect in NADPH oxidase fail to induce either actin and tubulin polymerization or NET formation on activation. Moreover, neutrophils deficient in glutaredoxin 1 (Grx1), an enzyme required for deglutathionylation of actin and tubulin, are unable to polymerize either cytoskeletal network and fail to degranulate or release DNA. Collectively, cytoskeletal dynamics are achieved as a balance between reactive oxygen species-regulated effects on polymerization and glutathionylation on the one hand and the Grx1-mediated deglutathionylation that is required for NET formation on the other.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / genetics
Actins / immunology
Animals
Cell Degranulation / drug effects
Cell Degranulation / immunology
Cytoskeleton / immunology*
Cytoskeleton / ultrastructure
DNA, Mitochondrial / immunology
DNA, Mitochondrial / metabolism
Extracellular Traps / chemistry
Extracellular Traps / drug effects
Extracellular Traps / immunology*
Gene Expression Regulation
Glutaredoxins / genetics
Glutaredoxins / immunology
Glutathione / immunology*
Glutathione / metabolism
Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
Homeodomain Proteins / immunology
Humans
Mice
Mice, Transgenic
NADPH Oxidases / genetics
NADPH Oxidases / immunology
Neutrophils / cytology
Neutrophils / drug effects
Neutrophils / immunology*
Oxidation-Reduction
Primary Cell Culture
Reactive Oxygen Species / immunology*
Reactive Oxygen Species / metabolism
Signal Transduction
Tubulin / genetics
Tubulin / immunology
Wiskott-Aldrich Syndrome Protein / deficiency
Wiskott-Aldrich Syndrome Protein / genetics
Wiskott-Aldrich Syndrome Protein / immunology

Substances

Actins
DNA, Mitochondrial
Glutaredoxins
HOXB8 protein, human
Homeodomain Proteins
Reactive Oxygen Species
Tubulin
WAS protein, human
Wiskott-Aldrich Syndrome Protein
Granulocyte-Macrophage Colony-Stimulating Factor
NADPH Oxidases
Glutathione

Associated data

RefSeq/NM_001101