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Updated: Jun 26, 2025

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Transient caspase-mediated activation of caspase-activated DNase causes DNA damage required for phagocytic macrophage

Deepak Maurya1, Gayatri Rai1, Debleena Mandal1

  • 1Cytogenetics Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, India.

Cell Reports
|May 18, 2024
PubMed

Insights

This study reveals that controlled DNA damage from caspase-activated DNase (CAD) is vital for macrophage differentiation and function. This process, regulated by insulin signaling, ensures proper innate immunity and tissue repair.

Area of Science:

  • Immunology
  • Developmental Biology
  • Cell Biology

Background:

  • Macrophages are essential for innate immunity and tissue homeostasis.
  • Most tissue-resident macrophages originate from embryonic precursors and self-renew throughout life.
  • The precise mechanisms governing diverse macrophage differentiation remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying versatile macrophage differentiation.
  • To investigate the role of caspase-activated DNase (CAD) in macrophage development.
  • To explore the involvement of insulin signaling pathways in regulating macrophage differentiation.

Main Methods:

  • In vivo genetic and cell biological analysis in Drosophila melanogaster.
  • Study of the Drosophila larval lymph gland, a hematopoietic organ.
  • Analysis of the insulin receptor-mediated PI3K/Akt signaling pathway and its regulation of the Ask1/JNK axis.

Main Results:

  • Developmentally regulated, transient activation of CAD-mediated DNA strand breaks in progenitor cells is essential for macrophage differentiation.
  • Insulin receptor-mediated PI3K/Akt signaling controls sublethal caspase activation, leading to DNA strand breaks during macrophage development.
  • Caspase activity is also crucial for the development of embryonic-origin macrophages and efficient phagocytosis.

Conclusions:

  • Transient DNA strand breaks mediated by CAD are a key mechanism for macrophage differentiation.
  • Sublethal caspase activation, regulated by insulin signaling, plays a critical role in macrophage development.
  • This research offers insights into developmental signaling and DNA damage in generating multifunctional and heterogeneous macrophages.
Keywords:
CAD/ICADCP: ImmunologyDraperDrosophilacaspasehematopoiesisintermediate progenitor cellslymph glandmyeloid progenitorsγH2Av

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