Casu, C. | Search bioRxiv

bioRxiv2021

The Hepcidin Regulator Erythroferrone is a New Member of the Erythropoiesis-Iron-Bone Circuitry

Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis. We report that ERFE expression in osteoblasts is higher compared with erythroblasts, is independent of erythropoietin, and functional in suppressing hepatocyte hepcidin expression. Erfe-/- mice display low-bone-mass arising from increased bone resorption despite a concomitant increase in bone formation. Consistently, Erfe-/- osteoblasts exhibit enhanced mineralization, Sost and Rankl expression, and BMP-mediated signaling ex vivo. The ERFE effect on osteoclasts is mediated through increased osteoblastic RANKL and sclerostin expression, increasing osteoclastogenesis in Erfe-/- mice. Importantly, Erfe loss in {beta}-thalassemic (Hbbth3/+) mice, a disease model with increased ERFE expression, triggers profound osteoclastic bone resorption and bone loss. Together, ERFE exerts an osteoprotective effect by modulating BMP signaling in osteoblasts, decreasing RANKL production to limit osteoclastogenesis, and prevents excessive bone loss during expanded erythropoiesis in {beta}-thalassemia.

physiology↗

bioRxiv2021

Red Blood Cells Function as DNA Sensors

Erythrocytes have long been mistaken as exclusively inert oxygen carriers lacking immune function. Here we show that red blood cells (RBCs) serve as immune sensors through surface expression of the nucleic acid-sensing toll-like receptor 9 (TLR9), a classically endosomal receptor that initiates immune responses following the detection of unmethylated CpG motifs present in pathogen and mitochondrial DNA. Mammalian RBCs express TLR9 on their surface and bind CpG-containing bacterial, malarial, and mitochondrial DNA. Erythrocyte-bound CpG DNA increases during infection, and CpG-carrying RBCs trigger accelerated erythrophagocytosis and innate immune activation characterized by RBC-TLR9 dependent local and systemic cytokine production. Thus, RBC nucleic acid detection and capture regulates red cell clearance and immune responses and provides evidence for RBCs as innate immune sentinels during pathologic states. One Sentence SummaryThe ability of RBCs to detect and bind cell-free nucleic acids contributes to immunity during acute inflammatory states.

immunology↗