Impact of aging on monocyte subset production by bone marrow progenitors

Abstract

Abstract Monocytes can patrol the circulation or be recruited into tissues to become macrophages or monocyte-derived dendritic cells (moDCs). We previously showed that monocytes arise via two independent pathways in mouse bone marrow: Granulocyte-Monocyte Progenitors (GMPs) produce neutrophils and monocytes, and Monocyte-DC Progenitors (MDPs) yield monocytes and conventional and plasmacytoid DCs (cDCs and pDCs). Notably, both pathways produce monocytes that can differentiate into macrophages, but moDCs arise exclusively via the MDP pathway. We also showed that the microbial stimuli LPS and CpG promote monocyte production by GMPs and MDPs, respectively. We are now investigating how aging impacts the balance of monocyte production by GMPs and MDPs. scRNAseq analysis revealed elevated Cd74 and H2 gene expression by steady-state classical monocytes from old mice compared to young mice, with a larger proportion of monocytes expressing these genes. Consistent with this, we observed proportionally more monocytes expressing CD74 and MHCII in the bone marrow and circulation of old mice by flow cytometry, and a higher yield of CD11c+ MHCII+ moDCs in GM-CSF cultures of MDPs and monocytes from old bone marrow. These findings are indicative of elevated moDC production during aging, perhaps reflecting the more inflammatory microenvironment. In ongoing studies, we are investigating whether imbalanced monocyte production by the GMP and MDP pathways underlies increased moDC production during aging.