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Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
09:04

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells

Published on: May 22, 2014

A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages

Abigail J Morales1, Javier A Carrero2, Putzer J Hung2

  • 1Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York City, United States.

Elife
|April 1, 2017
PubMed

Insights

Genotoxic agents in macrophages cause DNA damage, activating kinases that regulate immune responses. This DNA damage response is initiated by type I interferon signaling, impacting inflammasome activation and cytokine production.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Macrophages produce genotoxic agents (reactive oxygen and nitrogen species) to combat pathogens.
  • These agents can induce DNA damage within macrophages.

Purpose of the Study:

  • To investigate how genotoxic agents activate DNA damage response (DDR) kinases in macrophages.
  • To elucidate the role of type I interferon signaling in initiating this DDR.
  • To understand the downstream immune functions regulated by this DDR pathway.

Main Methods:

  • Analysis of DNA double-strand breaks (DSBs) in murine macrophage genomic DNA.
  • Assessment of DDR kinase activation (ATM and DNA-PKcs).
  • Investigation of type I interferon receptor signaling.
  • Evaluation of inflammasome activation and cytokine production (IL-1β, IL-18).
  • Study of immune cell interactions, including NK cell IFN-γ production, using gene-deficient macrophages.

Main Results:

  • Genotoxic agents activate ATM and DNA-PKcs via DSBs in murine macrophages.
  • Initiation of this DDR is dependent on type I interferon receptor signaling.
  • Activated kinases regulate immune functions, including inflammasome activation and IL-1β/IL-18 production.
  • DNA-PKcs-deficient macrophages show reduced IL-18 and impaired NK cell IFN-γ stimulation after Listeria monocytogenes infection.

Conclusions:

  • Genomic DNA DSBs serve as signaling intermediates in macrophages.
  • A type I interferon-dependent DDR pathway regulates innate immune responses.
  • This pathway is crucial for inflammasome activation and cytokine production, influencing adaptive immunity.
Keywords:
DNA damage responsesType I IFNimmunologyinflammasomemacrophage

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