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Bcl6, Irf2, and Notch2 promote nonclassical monocyte development.

Kevin W O'Connor1, Tiantian Liu1, Sunkyung Kim1

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Proceedings of the National Academy of Sciences of the United States of America
|August 22, 2023
PubMed
Summary
This summary is machine-generated.

NOTCH2 signaling, triggered by delta-like ligand 1 (DLL1), promotes Ly6Clo monocyte development from Ly6Chi monocytes. This process requires IRF2 and influences TREML4 expression, revealing a transcriptional hierarchy.

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Bcl6IRF2Notch2nonclassical monocytes

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Ly6Clo monocytes are crucial for vascular endothelium surveillance.
  • Ly6Clo monocytes are known to develop from Ly6Chi monocytes.
  • NOTCH2 signaling is implicated in Ly6Clo monocyte development, but the underlying mechanisms are unclear.

Purpose of the Study:

  • To investigate the role of NOTCH2 signaling in myeloid progenitors on Ly6Clo monocyte development.
  • To elucidate the transcriptional requirements for Ly6Clo monocyte differentiation.

Main Methods:

  • In vitro culture of myeloid progenitors.
  • NOTCH2 signaling induction using delta-like ligand 1 (DLL1).
  • Analysis of monocyte subset transition and gene expression (TREML4, BCL6, IRF2, NUR77).

Main Results:

  • DLL1-induced NOTCH2 signaling promoted the transition of Ly6Chi TREML4- monocytes to Ly6Clo TREML4+ monocytes.
  • BCL6 deletion abrogated Ly6Clo monocyte development.
  • IRF2 was essential for Ly6Clo monocyte development in a cell-intrinsic manner.
  • DLL1-induced transition required IRF2 but not necessarily BCL6 or NUR77.

Conclusions:

  • NOTCH2 signaling, via DLL1, drives Ly6Clo monocyte development.
  • IRF2 is a critical transcription factor for Ly6Clo monocyte differentiation.
  • A transcriptional hierarchy involving BCL6, IRF2, and NUR77 regulates Ly6Clo monocyte development.