Aged marrow macrophages expand platelet-biased hematopoietic stem cells via interleukin-1B

The bone marrow microenvironment contributes to the regulation of hematopoietic stem cell (HSC) function, though its role in age-associated lineage skewing is poorly understood. Here we show that dysfunction of aged marrow macrophages (M phi s) directs HSC platelet bias. M phi s from the marrow of aged mice and humans exhibited an activated phenotype, with increased expression of inflammatory signals. Aged marrow M phi s also displayed decreased phagocytic function. Senescent neutrophils, typically cleared by marrow M phi s, were markedly increased in aged mice, consistent with functional defects in M phi phagocytosis and efferocytos is. In aged mice, interleukin-1B (IL-1B) was elevated in the bone marrow, and caspase-1 activity, which can process pro-IL-1B, was increased in marrow M phi s and neutrophils. Mechanistically, IL-1B signaling was necessary and sufficient to induce a platelet bias in HSCs. In young mice, depletion of phagocytic cell populations or loss of the efferocytic receptor Axl expanded platelet-biased HSCs. Our data support a model wherein increased inflammatory signals and decreased phagocytic function of aged marrow M phi s induce the acquisition of platelet bias in aged HSCs. This work highlights the instructive role of M phi s and IL-1B in the age-associated lineage skewing of HSCs, and reveals the therapeutic potential of their manipulation as antigeronic targets.