M-CSF supports medullary erythropoiesis and erythroid iron demand following burn injury through its activity on homeostatic iron recycling

Abstract

M-CSF receptor signaling supports the development and survival of mononuclear phagocytes and is thought to play a role in post burn anemia by promoting myeloid lineage bias. We found M-CSF secretion was increased in burn patients and a murine model of post burn ACI, so we neutralized M-CSF in ACI mice to determine if erythropoiesis was improved. Instead, M-CSF blockade further impaired erythropoiesis and erythroid cells access to iron. M-CSF blockade enhanced inflammatory cytokine secretion, further increased systemic neutrophil counts, and led to tissue iron sequestration that was dependent, in part, on augmented IL-6 secretion which induced hepcidin. Deleterious effects of post burn M-CSF blockade were associated with arrest of an iron recycling gene expression signature in the liver and spleen that included Spi-C transcription factor and heme oxygenase-1, which promote heme metabolism and confer a non-inflammatory tone in macrophages. Hepatic induction of these factors in ACI mice was consistent with a recovery of ferroportin gene expression and reflected an M-CSF dependent expansion and differentiation of Spi-C+ monocytes into Kupffer cells. Together, this data indicates M-CSF secretion supports a homeostatic iron recycling program that plays a key role in the maintenance of erythroid cells access to iron following burn injury.

Identification of ferroptosis-related genes and predicted overall survival in patients with burns

“…GSEA, Gene Set Enrichment Analysis; GSVA, Gene Set Variation Analysis. response to the increased destruction of red blood cells (48). Meanwhile, GSEA showed that SLC40A2 enrichment was immune-related, including pathways of antigen processing and presentation (the most significant downward adjustment in GSVA), graft vs. host disease, the intestinal immune network for IgA production, NK cell-mediated cytotoxicity, etc.…”

“…Burn injury induces an macrophage colony-stimulating factor (M-CSF)-dependent iron recycling program in the liver and spleen, and iron transporter expression recovered over time. This may be an iron homeostasis response to the increased destruction of red blood cells ( 48 ). Meanwhile, GSEA showed that SLC40A2 enrichment was immune-related, including pathways of antigen processing and presentation (the most significant downward adjustment in GSVA), graft vs. host disease, the intestinal immune network for IgA production, NK cell-mediated cytotoxicity, etc.…”