IL-1/MyD88-Dependent G-CSF and IL-6 Secretion Mediates Postburn Anemia

The anemia of critical illness (ACI) is a nearly universal pathophysiological consequence of burn injury and a primary reason burn patients require massive quantities of transfused blood. Inflammatory processes are expected to drive postburn ACI and prevent meaningful erythropoietic stimulation through iron or erythropoietin supplementation, but to this day no specific inflammatory pathways have been identified as a critical mechanism. In this study, we examined whether secretion of G-CSF and IL-6 mediates distinct features of postburn ACI and interrogated inflammatory mechanisms that could be responsible for their secretion. Our analysis of mouse and human skin samples identified the burn wound as a primary source of G-CSF and IL-6 secretion. We show that G-CSF and IL-6 are secreted independently through an IL-1/MyD88-dependent mechanism, and we ruled out TLR2 and TLR4 as critical receptors. Our results indicate that IL-1/MyD88-dependent G-CSF secretion plays a key role in impairing medullary erythropoiesis and IL 6 secretion plays a key role in limiting the access of erythroid cells to iron. Importantly, we found that IL-1a/b neutralizing Abs broadly attenuated features of postburn ACI that could be attributed to G-CSF or IL-6 secretion and rescued deficits of circulating RBC counts, hemoglobin, and hematocrit caused by burn injury. We conclude that wound-based IL-1/MyD88 signaling mediates postburn ACI through induction of G-CSF and IL-6 secretion. The Journal of Immunology, 2023, 210: 972-980.

Automated summary

This study demonstrates that the burn wound is the primary source of G-CSF and IL-6 secretion, and their secretion is independent through an IL-1/MyD88-dependent mechanism. IL-1/MyD88 signaling mediates postburn anemia by inducing G-CSF and IL-6 secretion, leading to impaired medullary erythropoiesis and limiting the access of erythroid cells to iron. Neutralizing IL-1a/b antibodies attenuate features of postburn anemia and restore deficits caused by burn injury.