Abstract
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 Ly6Chi and Ly6Clo 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 Ly6Clo 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 Ly6Chi 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.