Genetics and cell biology
Regulation of iron metabolism
The Regulation of iron metabolism Unit is interested in dissecting the complex mechanism/s that control systemic iron regulation both in physiologic and in pathologic conditions. The latter include genetic forms of Hereditary Hemochromatosis and ineffective erythropoiesis as Thalassemias, acquired forms of anemia (as Anemia of Inflammation, Chronic Kideny Disease and Malaria infection) and metabolic disorders (as Non Alcoholic Fatty Liver Disease, NAFLD).
Over the years the unit has strongly contributed to unravel the role of different players in the control of the hepcidin/ferroportin axis, the main regulator of iron absorption and recycling, and in the crosstalk between the liver, the main organ in the regulation of iron/hepcidin, and erythroid cells, the main consumer of iron.
More in detail, investigating the crosstalk between hepcidin and erythropoiesis, we have defined the role of the second transferrin receptor (TFR2). Homologous to the ubiquitous TFR1, TFR2 is mainly expressed in hepatocytes and erythroid precursors. Hepatic TFR2 contributes to hepcidin activation and its inactivation leads to hemochromatosis, while erythroid TFR2 interacts with Erythropoietin receptor (EPOR) and acts as a brake of EPO signaling, thus controlling the production of erythrocytes.
We recently proved that bone marrow Tfr2 deletion causes erythropoietin-independent erythrocytosis and ameliorates anemia in non-transfusion dependent beta-thalassemic mice. Trying to dissect the mechanism of liver hepcidin regulation, the team has recently identified a new level of hepcidin control mediated by the immunophilin FKBP12, which binds to and inhibits the BMP receptor ALK2, thus negatively regulating hepcidin transcription. FKBP12 targeting in vivo could be a promising therapeutic approach to several hepcidin-related diseases as Hemochromatosis and Thalassemia.
- How does TFR2 regulate hepcidin expression in hepatocytes and EPOR signaling in erythroid cells? Exploiting in vitro, ex vivo and in vivo models we are investigating the molecular mechanism of TFR2-mediated hepcidin upregulation in hepatocytes and the role of TFR2 as a modulator of EPOR processing, function and signaling in erythroid cells.
- Exploring TFR2 as a therapeutic target for anemia. We are capitalizing on the new knowledge of the role of TFR2 as a brake of erythropoiesis to boost erythroid response in congenital and acquired anemias, as β-thalassemia, anemia of inflammation, anemia of chronic kidney disease and malarial anemia.
- How does FKBP12 regulate the BMP-SMAD signaling pathway and hepcidin expression? We are exploring the FKBP12 mechanistic function, its relationship with homo and heterodimeric BMP type I and II receptors and the effect of its liver selective inactivation, as a novel potential therapeutic approach for disorders characterized by hepcidin insufficiency.
- Exploring the role of liver and skeletal muscle BMP-SMAD pathway and liver hepcidin regulation in NAFLD and its complication steatohepatitis (NASH). A close correlation between iron and lipid metabolism is suggested by the observation of altered iron status in obesity and NAFLD. In addition, the crosstalk between liver and skeletal muscle plays a role in disease progression. We are exploring whether the hepatic targeting of methyltransferases SUV420H1/2 is protective against diet-induced NAFLD by upregulation of PPARα/hepcidin target genes and more interestingly, whether their selective downregulation improves non alcoholic steatohepatitis (NASH). Since a decrease in muscle mass is a common feature in NAFLD-NASH and likely involved in disease progression, we are also investigating whether muscle improvement by activation of the BMP-SMAD pathway in this selected tissue can ameliorate the NAFLD-NASH phenotype
Nai A., Lorè N.I., Pagani A., De Lorenzo R., Di Modica S., Saliu F., Cirillo D.M., Rovere-Querini P., Manfredi A.A. and Silvestri L. Hepcidin levels predict Covid-19 severity and mortality in a cohort of hospitalized Italian patients. Am J Hematol. 2020;96(1):E32-35.
Casu C., Pettinato M., Liu A., Aghajan M., Lo Presti V., Lidonnici M.R., Munoz K.A., O’Hara E., Olivari V., Di Modica S.M., Booten S., Guo S., Neil G., Miari R., Shapir N., Zafir-Lavie I., Domev H., Ferrari G., Sitara D., Nai A. and Rivella S. Correcting β-thalassemia by combined therapies that restrict iron and modulate erythropoietin activity. Blood. 2020;136(17):1968-79.
Nai A., Lidonnici M.R., Federico G., Pettinato M., Olivari V., Carrillo F., Geninatti-Crich S., Ferrari G., Camaschella C., Silvestri L. and Carlomagno F. NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice. Haematologica. 2021;106(3):795-805.
Pagani A., Pettinato M., Colucci S., Dulja A., Rauner M., Nai A., Camaschella C., Altamura S., Muckenthaler M.U. and Silvestri L. Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2. Haematologica. 2020;105(10):241984.
Artuso I., Pettinato M., Nai A., Pagani A., Sardo U., Billoré B., Lidonnici MR., Bennett C., Mandelli G., Pasricha SR., Ferrari G., Camaschella C., Kautz L. and Silvestri L. Transient decrease of serum iron after acute erythropoietin treatment contributes to hepcidin inhibition by ERFE in mice. Haematologica. 2018;104(3):387-90.
Artuso I., Lidonnici M.R., Altamura S., Mandelli G., Pettinato M., Muckenthaler M.U., Silvestri L., Ferrari G., Camaschella C., Nai A. Transferrin receptor 2 is a potential novel therapeutic target for β- thalassemia: evidence from a murine model. Blood. 2018;132(21):2286-2297.
Colucci S., Pagani A., Pettinato M., Artuso I., Nai A., Camaschella C., Silvestri L. The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes. Blood. 2017;130(19):2111-2120.
Nai A., Rubio A., Campanella A., Gourbeyre O., Artuso I., Bordini J., Gineste A., Latour C., Besson-Fournier C., Lin H.Y., Coppin H., Roth M.P., Camaschella C., Silvestri L., Meynard D. Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice. Blood. 2016;127(19):2327-36.
Rausa M., Pagani A., Nai A., Campanella A., Gilberti M.E., Apostoli P., Camaschella C. and Silvestri L. Bmp6 expression in murine liver non parenchimal cells: a mechanism to control their high iron exporter activity and protect hepatocytes from iron overload? PLoS One. 2015;10(4):e0122696.
Pagani A., Voeillevoye M., Nai A., Rausa M., Ladli M., Lacombe C., Mayeux P., Verdier F., Camaschella C. and Silvestri L. Regulation of cell surface transferrin receptor-2 by iron-dependent cleavage and release of a soluble form. Haematologica. 2015;100(4):458-65.
Nai A, Lidonnici MR, Rausa M, Mandelli G, Pagani A, Silvestri L, Ferrari G, Camaschella C. The second transferrin receptor regulates red blood cell production in mice. Blood. 2015;125(7):1170-9.
Nai A, Pagani A, Mandelli G, Lidonnici MR, Silvestri L, Ferrari G, Camaschella C. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta- thalassemia. Blood. 2012;119(21):5021-9.
Nai A., Pagani A., Silvestri L., Campostrini N., Corbella M., Girelli D., Traglia M., Toniolo D. and Camaschella C. TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. Blood. 2011;118(16):4459-62.
Silvestri L., Guillem F., Pagani A., Nai A., Oudin C., Silva M., Toutain F., Kannengiesser C., Beaumont C., Camaschella C. and Grandchamp B. Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood. 2009;113 (22): 5605-08 (2009).
Silvestri L., Pagani A., Nai A., De Domenico I., Kaplan J. and Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Met. 2008;8 (6): 502-11.
Silvestri L, Pagani A, Fazi C, Gerardi G, Levi S, Arosio P, Camaschella C. Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis. Blood. 2007;109(10):4503-10.