Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 120, Issue 35, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2220853120
Keywords
nonclassical monocytes; Bcl6; IRF2; Notch2
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This study investigates the impact of NOTCH2 signaling on the development of Ly6C(lo) monocytes and identifies transcription factors involved. The results show that NOTCH2 signaling can induce the transition of Ly6C(hi) monocytes into Ly6C(lo) monocytes, and that BCL6 and IRF2 are important for this development process.
Ly6C(lo) monocytes are a myeloid subset that specializes in the surveillance of vascular endothelium. Ly6C(lo) monocytes have been shown to derive from Ly6C(hi) monocytes. NOTCH2 signaling has been implicated as a trigger for Ly6C(lo) monocyte development, but the basis for this effect is unclear. Here, we examined the impact of NOTCH2 signaling of myeloid progenitors on the development of Ly6C(lo) monocytes in vitro. NOTCH2 signaling induced by delta-like ligand 1 (DLL1) efficiently induced the transition of Ly6C(hi) TREML4(-) monocytes into Ly6C(lo) TREML4(+) monocytes. We further identified two additional transcriptional requirements for development of Ly6C(lo) monocytes. Deletion of BCL6 from myeloid progenitors abrogated development of Ly6C(lo) monocytes. IRF2 was also required for Ly6C(lo) monocyte development in a cell-intrinsic manner. DLL1-induced in vitro transition into Ly6C(lo) TREML4(+) monocytes required IRF2 but unexpectedly could occur in the absence of NUR77 or BCL6. These results imply a transcriptional hierarchy for these factors in controlling Ly6C(lo) monocyte development.
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