Thermal injury of the skin induces G-CSF-dependent attenuation of EPO-mediated STAT signaling and erythroid differentiation arrest in mice.

Inflammation-mediated impairment of erythropoiesis plays a central role in the development of the anemia of critical illness (ACI). ACI develops despite elevation of endogenous erythropoietin (EPO), does not respond to exogenous erythropoietin (EPO) supplementation, and contributes significantly to transfusion requirements in burned patients. We have reported previously that the reduction of red blood cell mass in the bone marrow of a burn-injured ACI mouse model is granulocyte colony-stimulating factor (G-CSF) dependent. Given that elevated G-CSF levels also have been associated with lower hemoglobin levels and increased transfusion requirements in trauma victims, we postulated that G-CSF mediates postburn EPO resistance. In ACI mice, we found that bone marrow erythroid differentiation, viability, and proliferation are impaired after thermal injury of the skin. These changes in the marrow were associated with attenuated phosphorylation of known EPO-responsive signaling nodes, signal transducer and activator of transcription 5 (STAT5) Y694 and STAT3 S727, in bone marrow erythroid cells and developed despite highly elevated levels of endogenous EPO. Severely blunted STAT5 Y694 phosphorylation in bone marrow erythroid cells after exogenous EPO supplementation confirmed that EPO signaling was impaired in ACI mice. Importantly, parenteral administration of anti-G-CSF largely rescued postburn bone marrow erythroid differentiation arrest and EPO signaling in erythroid cells. Together, these data provide strong evidence for a role for G-CSF in the development of ACI after burn injury through suppression of EPO signaling in bone marrow erythroid cells.