3054 – MONOCYTE SUBSET PRODUCTION DURING AGING

Abstract

A growing body of evidence suggests that monocytes are more heterogenous than previously appreciated and that monocyte subsets play distinct roles in both health and disease. We have previously demonstrated that two separate pathways of monocyte production by granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) yield functionally distinct monocyte subsets in mouse bone marrow. GMPs produce classical monocytes with neutrophil-like properties, and MDPs yield classical monocytes that give rise to monocyte-derived DCs (moDCs). We also showed that Toll-like receptor agonists differentially promote production of these monocyte subsets during emergency monopoiesis. Aging induces a myeloid bias leading to increased monocyte output by the bone marrow. However, it is unclear whether the GMP and MDP pathways both contribute to increased monocyte output during aging. We observed myeloid-biased hematopoiesis in the bone marrow of old mice and elevated classical monocytes in the circulation, recapitulating previous reports. Single cell RNA-sequencing revealed an increased proportion of classical monocytes expressing MHC II molecules (H2-A and H2-E genes) and Cd74 in the bone marrow of old mice. We also observed a higher frequency of MHC II-expressing monocytes in the bone marrow and blood of old mice by flow cytometry. Together the data suggest that production of moDCs by MDPs is enhanced during aging. We are also investigating whether infection and acetaminophen-induced liver injury alter the balance of monocyte subsets that promote inflammation and tissue damage versus tissue repair and regeneration.