Systematic monocyte subset analysis reveals differential contribution of Notch signaling components to monocyte heterogeneity

Iscience: Volume 28, Issue 11, Page 113795

Monocyte heterogeneity and plasticity create a spectrum of phagocytes essential for innate immune functions, which is partially regulated by Notch signaling. Using systematic monocyte subset analysis in different compartments, we here confirm that monocyte heterogeneity extends beyond the Ly6C(hi) and Ly6C(lo) monocytes and is regulated by Notch. Employing different monocyte-lineage-development-specific Cre-deleter strains in combination with conditional alleles for the receptor Notch2 or the Notch nuclear mediator Rbpj, we also show that subset development is differentially regulated by Notch-signaling components. Deletion of Notch2 broadly affects development of Ly6C(lo) monocytes, or related monocyte subsets, and alters monocyte phenotypes, while deletion of Rbpj has more restricted effects, mostly on monocyte phenotypes. Furthermore, the developmental plasticity of Ly6C(hi) monocyte subsets in vitro is regulated by Notch2 but dependent on the context of specific Notch ligand and myeloid growth factor. Thus, Notch signaling components differentially regulate monocyte heterogeneity and plasticity.

DOI: 10.1016/j.isci.2025.113795