IL-17A primes an early progenitor compartment to tune the erythropoietic feedback circuit

Feedback control of erythropoiesis exemplifies conflicting goals in tissue homeostasis: maintaining fast reactivity to stress while minimizing proliferative burden on progenitors in the steady state. Here we show that these conflicting goals are tuned through the combinatorial action of cytokines. We find that IL-17A, a pro-inflammatory cytokine, mediates striking synergism with the negative feedback signal erythropoietin (Epo) in vivo, accelerating the erythropoietic response to hypoxia. A model of erythropoietic control shows increased reactivity may occur through two cell circuit designs, with one having far lower constitutive progenitor burden in normoxia. IL-17A acts through this optimal design by sensitizing progenitors to Epo, a model supported by multiple experimental observations. We suggest that IL-17A signals impending hypoxia during infections, tuning erythropoiesis in favor of a faster stress response. Our study highlights IL-17A as a potential erythropoietic therapeutic agent and serves as a model of homeostatic tuning in stem and progenitor cell circuits.