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ROS and DNA repair in spontaneous versus agonist-induced NETosis: Context matters.

Dhia Azzouz1,2, Nades Palaniyar1,2,3

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Reactive oxygen species (ROS) drive neutrophil extracellular trap formation (NETosis). DNA repair mechanisms differentially regulate spontaneous and agonist-induced NETosis, with early repair inhibiting and late-stage repair promoting NETosis.

Keywords:
DNA polymerasesDNA repairNADPH oxidase (NOX)base excision repair (BER)neutrophil extracellular traps (NETs)proliferating cell nuclear antigen (PCNA)reactive oxygen species (ROS)spontaneous NETosis

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Reactive oxygen species (ROS) are crucial for neutrophil extracellular trap formation (NETosis).
  • The precise mechanisms by which ROS induce NETosis, particularly at baseline versus during activation, remain unclear.
  • The role of DNA transcription, replication, and repair machineries in mature neutrophils has been a long-standing mystery.

Purpose of the Study:

  • To elucidate the differential roles of DNA repair pathways in spontaneous and agonist-induced NETosis.
  • To investigate how reactive oxygen species (ROS) and oxidative DNA damage influence NETosis.
  • To determine the necessity of specific DNA repair proteins in chromatin decondensation during NETosis.

Main Methods:

  • Investigated the effects of inhibiting early and late-stage oxidative DNA damage repair proteins on NETosis.
  • Utilized NETosis-inducing agonists and NADPH oxidase activating agonists to generate varying levels of ROS.
  • Monitored chromatin decondensation and NETosis in response to specific DNA repair protein inhibition.

Main Results:

  • Inhibition of early DNA repair steps (PARP, APE1, DNA ligase) suppressed spontaneous NETosis.
  • Inhibition of late-stage DNA repair proteins (PCNA, DNA Polymerases) drastically promoted baseline NETosis.
  • Oxidative DNA damage (8-oxy-guanine) and initial DNA repair steps are required for agonist-induced NETosis-associated chromatin decondensation.

Conclusions:

  • DNA repair pathways play distinct roles in regulating spontaneous versus agonist-induced NETosis.
  • In the absence of significant ROS and neutrophil activation, DNA repair by PCNA and DNA polymerases prevents spontaneous NETosis.
  • ROS, oxidative DNA damage, transcription, and DNA repair are context-dependent regulators of NETosis.