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Iron Metabolism & its Disorders
C-FGF23 peptide alleviates hypoferremia during acute inflammation
Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):391-403
Rafiou Agoro,1 Min Young Park,1 Carole Le Henaff,1 Stanislovas Jankauskas,1 Alina Gaias,1 Gaozhi Chen,2 Moosa Mohammadi3 and Despina Sitara1,4
1Department of Basic Science and Craniofacial Biology, NYU College of Dentistry, New York, NY, USA; 2Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China; 3Departments of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA and 4Department of Medicine, NYU School of Medicine, New York, NY, USA
ABSTRACT
Hypoferremia results as an acute phase response to infection and inflammation aiming to reduce iron availability to pathogens. Activation of toll-like receptors (TLR), the key sensors of the innate immune system, induces hypoferremia mainly through the rise of the iron hormone hepcidin. Conversely, stimulation of erythropoiesis suppresses hepcidin expression via induction of the erythropoietin-responsive hor- mone erythroferrone. Iron deficiency stimulates transcription of the osteo- cyte-secreted protein FGF23. Here we hypothesized that induction of FGF23 in response to TLR4 activation is a potent contributor to hypofer- remia and, thus, impairment of its activity may alleviate hypoferremia induced by lipopolysaccharide (LPS), a TLR 4 agonist. We used the C-termi- nal tail of FGF23 to impair endogenous full-length FGF23 signaling in wild- type mice, and investigated its impact on hypoferremia. Our data show that FGF23 is induced as early as pro-inflammatory cytokines in response to LPS, followed by upregulation of hepcidin and downregulation of erythropoietin (Epo) expression in addition to decreased serum iron and transferrin satura- tion. Further, LPS-induced hepatic and circulating hepcidin were significant- ly reduced by FGF23 signaling disruption. Accordingly, iron sequestration in liver and spleen caused by TLR4 activation was completely abrogated by FGF23 signaling inhibition, resulting in alleviation of serum iron and trans- ferrin saturation deficit. Taken together, our studies highlight for the first time that inhibition of FGF23 signaling alleviates LPS-induced acute hypo- ferremia.
Introduction
Hypoferremia develops as a response to innate immune system activation follow- ing inflammation or infection. Iron is an essential element required for the survival, proliferation, and virulence of pathogens. The hypoferremic response is an impor- tant defense mechanism that aims to prevent iron bioavailability to pathogens by sequestration of iron within macrophages, resulting in a significant reduction in cir- culating iron levels.1-3 Toll-like receptors (TLR) are key components of the innate immune system that recognize pathogen-associated molecular patterns (PAMP), and are responsible for sensing invading pathogens. Activation of TLR signaling plays a pivotal role in the development of the hypoferremic host response.2,3 Lipopolysaccharide (LPS), a PAMP that is the major component of the outer mem- brane of Gram-negative bacteria, is known to activate TLR4. Injection of LPS to mice or humans causes a rapid release of pro-inflammatory cytokines and triggers a well characterized acute phase inflammatory response followed by an induction of the hepatic hormone hepcidin, the central regulator of iron homeostasis.4-6
Hepcidin binds to ferroportin, the only known iron exporter, and causes its inter- nalization and degradation,7 resulting in iron sequestration in reticulo-endothelial macrophages, hepatocytes, and duodenal enterocytes, and subsequently decreased circulating iron levels.8 This situation of circulating iron restriction promotes ineffec- tive erythropoiesis and results in anemia of inflammation, a form of anemia common- ly associated with infectious diseases, cancer, and chronic kidney disease (CKD).9
Correspondence:
DESPINA SITARA
ds199@nyu.edu
Received: September 2, 2019. Accepted: March 13, 2020. Pre-published: March 19, 2020.
https://doi.org/10.3324/haematol.2019.237040
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