IL-17 stimulates erythropoiesis in vivo by amplifying the response of erythroid progenitors to erythropoietin

Red blood cell production is regulated by erythropoietin (Epo), maintaining tissue oxygen tension in the steady state and in response to stress. To date, only a handful of factors other than Epo are known to stimulate erythropoiesis, limiting therapeutic options. We recently found that IL-17, a pleiotropic pro-inflammatory cytokine, interacts synergistically with Epo to increase formation of erythroid colonies in vitro. Here, we administered IL-17 to mice to determine whether it accelerates erythropoiesis in vivo. We found that while IL-17 alone had little effect on erythroid and other hematopoietic lineages, combined treatment with both IL-17 and Epo generated a specific and strong synergistic response in erythroid progenitors that significantly increased erythropoietic rate. IL-17 administration also accelerated the erythropoietic response of mice to hypoxia. Single-cell transcriptomic analysis showed that IL-17 acts by sensitizing erythroid progenitors to Epo, rather than through a distinct transcriptional response. Using a dynamical model, we propose that this mechanism optimizes conflicting requirements in the regulation of erythropoiesis, balancing the need for low-cost maintenance of the steady state, with a sufficiently fast stress response. Further, our findings suggest a potentially broadly applicable mechanism whereby pleiotropic cytokines are able to exert lineage-specific effects when their actions are dependent on synergism with lineage-specific factors.