Bcl6, Irf2, and Notch2 promote nonclassical monocyte development

Bcl6, Irf2, and Notch2 promote nonclassical monocyte development

Contributed by Kenneth M. Murphy; received December 7, 2022; accepted July 28, 2023; reviewed by Dan R. Littman and Miriam Merad

August 22, 2023

120 (35) e2220853120

Significance

Nonclassical monocyte development is poorly understood, inhibiting studies of their function and efforts to target them therapeutically. We identify BCL6 and IRF2 as transcription factors required for nonclassical monocytes in mice. We additionally develop a Notch-mediated system modeling nonclassical monocyte development in vitro. This work deepens our understanding of how nonclassical monocytes arise and will support future work assessing the function and therapeutic potential of this cell type.

Abstract

Ly6Clo monocytes are a myeloid subset that specializes in the surveillance of vascular endothelium. Ly6Clo monocytes have been shown to derive from Ly6Chi monocytes. NOTCH2 signaling has been implicated as a trigger for Ly6Clo 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 Ly6Clo monocytes in vitro. NOTCH2 signaling induced by delta-like ligand 1 (DLL1) efficiently induced the transition of Ly6Chi TREML4 monocytes into Ly6Clo TREML4+ monocytes. We further identified two additional transcriptional requirements for development of Ly6Clo monocytes. Deletion of BCL6 from myeloid progenitors abrogated development of Ly6Clo monocytes. IRF2 was also required for Ly6Clo monocyte development in a cell-intrinsic manner. DLL1-induced in vitro transition into Ly6Clo 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 Ly6Clo monocyte development.

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Data, Materials, and Software Availability

RNA-seq data and microarray data are available on the Gene Expression Omnibus (GEO) database with the accession number GSE218504 (65).

Acknowledgments

We would like to acknowledge Charles Shen and Feiya Ou for assistance and technical advice regarding RNA-Seq. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. This work was supported by the NIH (R01AI150297, R01CA248919, R01AI162643, and R21AI164142 to K.M.M.)

Author contributions

K.W.O., C.G.B., T.L.M., and K.M.M. designed research; K.W.O., T.L., S.K., C.G.B., and T.L.M. performed research; K.W.O. and K.G. contributed new reagents/analytic tools; K.W.O., T.L., S.K., and C.G.B. analyzed data; and K.W.O., T.L.M., and K.M.M. wrote the paper.

Competing interests

The authors declare no competing interest.

Supporting Information

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences

Vol. 120 | No. 35
August 29, 2023

Classifications

Copyright

Data, Materials, and Software Availability

RNA-seq data and microarray data are available on the Gene Expression Omnibus (GEO) database with the accession number GSE218504 (65).

Submission history

Received: December 7, 2022

Accepted: July 28, 2023

Published online: August 22, 2023

Published in issue: August 29, 2023

Keywords

  1. nonclassical monocytes
  2. Bcl6
  3. IRF2
  4. Notch2

Acknowledgments

We would like to acknowledge Charles Shen and Feiya Ou for assistance and technical advice regarding RNA-Seq. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. This work was supported by the NIH (R01AI150297, R01CA248919, R01AI162643, and R21AI164142 to K.M.M.)

Author Contributions

K.W.O., C.G.B., T.L.M., and K.M.M. designed research; K.W.O., T.L., S.K., C.G.B., and T.L.M. performed research; K.W.O. and K.G. contributed new reagents/analytic tools; K.W.O., T.L., S.K., and C.G.B. analyzed data; and K.W.O., T.L.M., and K.M.M. wrote the paper.

Competing Interests

The authors declare no competing interest.

Notes

Reviewers: D.R.L., NYU Langone Health; and M.M., Icahn School of Medicine at Mount Sinai.

Authors

Affiliations

Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110

Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110

Sunkyung Kim

Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110

Carlos G. briseño

Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110

Present address: Department of Oncology, Amgen Inc., South San Francisco, CA 94080.

Katia Georgopoulos

Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114

Theresa L. Murphy

Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110

Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110

Notes

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