Iron is a fundamental element for life, even if in excess it could be toxic for its ability to generate reactive oxygen species. Iron is absorbed from the diet in the duodenum, released in circulation where, bound to the iron carrier transferrin, is delivered to the main sites of utilization (bone marrow for hemoglobin production and muscle cells for myoglobin synthesis) or storage (splenic macrophages and liver). Since no active mechanisms of iron excretion exist, iron absorption must be tightly regulated. The master regulator of iron metabolism is hepcidin, a peptide hormone produced by the liver in response to increased iron levels and released in circulation. Hepcidin binds the only known iron exporter ferroportin on the membrane of duodenal enterocytes and macrophages inducing its internalization and degradation. This blocks iron absorption from the diet and release from the stores.
Since in the body iron is mainly utilized by the bone marrow for red blood cells production, erythropoiesis controls iron homeostasis regulating the transcription of hepcidin. To signal their iron needs to the liver, erythroid cells release in the circulation erythroferrone, an EPO target gene that inhibits hepcidin through a still unknown mechanism, increasing iron availability for erythropoiesis.
In this context my main research interest is the elucidation of the crosstalk between iron metabolism and erythropoiesis and its manipulation for therapeutic purposes.
– January 2009-February 2013: PhD in Medicine and Experimental Therapy, Pharmacology and Experimental and Clinic Therapy, University of Turin, Italy
– September 2005-July 2007: Master of science in Molecular Biotechnology, 110/110 cum laude and special mention, University of Turin, Turin, Italy
– September 2002-July 2005: BS in Biomolecular Biotechnology, 110/110 cum laude, University of Turin, Turin, Italy
- Research activity
– January 2016 – present: senior post-doc, Ospedale San Raffaele (Milan, Italy)
– March 2013-December 2015: junior post-doc, Vita-Salute San Raffaele University (Milan, Italy)
– January 2009 – February 2013: PhD student, joint position between the University of Turin (Turin, Italy) and Vita-Salute San Raffaele University (Milan, Italy).
– November 2007- December 2008: post-graduate fellow, Vita-Salute San Raffaele University (Milan, Italy).
- Teaching activity
– From november 2015: Tutor of the course “Tecniche Sperimentali Molecolari-prima parte”, Vita-Salute San Raffaele University (Milan, Italy)
– Lab supervisor of Master and PhD students.
“Josè Carreras Non-Clinical Junior Research Fellowship” of the European Hematology Association (January 2016-December 2018)
“Under40 in Hematology 2013” Award, Turin, Italy, November 14-14, 2013
Best Oral Presentation Award (1st placed) of the EIC Meeting 2011, Louvain-la-Neuve, Belgium, September 8-10, 2011
Best Poster Award (3rd placed) of the EIC Meeting 2008, St. Gallen, Switzerland, September 17-19, 2008
“Premio Optime 2008” of the Industrial Union of Turin for the best thesis of the academic year 2006/2007
Transferrin receptor 2 (TFR2) is involved in systemic regulation of iron metabolism in the liver and modulates erythropoietin sensitivity in erythroid cells. When TFR2 is absent, the production of red blood cells and hemoglobin is increased and a mild iron-deficiency is mimicked. β-thalassemia is a disease due to mutations in the β-globin gene, characterized by anemia, ineffective erythropoiesis (IE), splenomegaly and secondary iron-overload. Several studies demonstrated that β-thalassemia phenotype is ameliorated by restriction of iron availability for erythropoiesis. For these reasons we hypothesize that Tfr2 deletion, enhancing erythropoiesis and simulating iron deficiency, improves the thalassemic phenotype. To verify this hypothesis we generated thalassemic mice with inactivation of Tfr2 in the whole organism or selectively in the bone marrow.
Preliminary results suggest that in both models deletion of Tfr2 significantly ameliorates anemia and IE of thalassemia intermedia mice. We will analyze more in detail the effect of Tfr2 deletion, in order to shed light on its molecular role on IE in β-thalassemia. Moreover we will modulate the iron phenotype of our mice to identify the role of iron in this system. The final goal is to test a selective inhibitor of Tfr2 in thalassemic animals to be proposed as a novel therapeutic agent to control IE and improve anemia of β-thalassemia in preclinical studies.
- 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.# and Meynard D.# Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice. In press. Blood. 127(19):2327-36 (2016). [* and # The authors contributed equally to the work].
- Pagani A., Ladli M., Nai A., Verdier F., Camaschella C. and Silvestri L. Comment on: PACE4 (PCSK6): another proprotein convertase linked to iron homeosyasis? Haematologica. 100:e380 (2015).
- 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. 10(4):e0122696 (2015).
- Rausa M., Ghitti M., Pagani A., Nai A., Campanella A., Musco G., Camaschella C. and Silvestri L. Identification of TMPRSS6 cleavage sites of hemojuvelin. J Cell Mol Med. 19(4):879-88 (2015).
- 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. 100(4):458-65 (2015).
- Nai A.*, Lidonnici M.R.*, Rausa M., Mandelli G., Pagani A., Silvestri L., Ferrari G. and Camaschella C. The second transferrin receptor regulates red blood cell production in mice. Blood. 125(7):1170-9 (2015). [*The authors contributed equally to the work].
- Nai A.*, Pellegrino R.M.*, Rausa M., Pagani A., Boero M., Silvestri L., Saglio G., Roetto A. and Camaschella C. The erythroid function of transferrin receptor 2 revealed Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice. Haematologica, 99(6):1016-21 (2014). [*The authors contributed equally to the work].
- Riba M., Rausa M., Sorosina M., Cittaro D., Martinelli-Boneschi F., Nai A., Pagani A., Camaschella C. and Silvestri L. A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6-/- mice. PLoS One, 8(7):e69694 (2013).
- Silvestri L., Rausa M., Pagani A., Nai A. and Camaschella C. How to assess causality of TMPRSS6 mutations? Hum Mutat., 34(7):1043-5 (2013).
- Nai A., Pagani A., Mandelli G., Lidonnici MR., Silvestri L., Ferrari G. and Camaschella C. Deletion of Tmprss6 attenuates the phenotype in a mouse model of β-thalassemia. Blood. 119(21):5021-9 (2012)
- 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. 118(16):4459-62 (2011)
- Pagani A.*, Nai A.*, Corna G., Bosurgi L., Rovere-Querini P., Camaschella C. and Silvestri L., Low hepcidin accounts for the proinflammatory status associated with iron deficiency. Blood. 118(3):736-46 (2011) [*The authors contributed equally to the work]
- Poli M., Girelli D., Campostrini N., Maccarinelli F., Finazzi D., Luscieti S., Nai A. and Arosio P., Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo. Blood. 117(3):997-1004 (2011)
- Nai A., Pagani A., Silvestri L. and Camaschella C., Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice. Blood. 116(5):851-2 (2010)
- De Falco L., Totaro F., Nai A., Pagani A., Girelli D., Silvestri L., Piscopo C., Campostrini N., Dufour C., Al Manjomi F., Minkov M., Van Vuurden DG, Feliu A., Kattamis A., Camaschella C. and Iolascon A. Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA). Hum Mutat. 31(5):E1390-405 (2010).
- 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, 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., 8 (6): 502-11 (2008).
- Pagani A., Silvestri L., Nai A., Camaschella C. Hemojuvelin N-terminal mutants reach the plasma membrane but do not activate the hepcidin response. Haematologica, 93 (10): 1466-72 (2008).
- Eva C., Mele P., Collura D., Nai A., Pisu MG., Serra M. and Biggio G. Modulation of neuropeptide Y and Y1 receptor expression in the amygdala by fluctuations in the brain content of neuroactive steroids during ethanol drinking discontinuation in Y1R/LacZ transgenic mice. J. Neurochem, 104(4):1043-54 (2008).
- Camaschella C., Pagani A., Nai A. and Silvestri L. The mutual control of iron and erythropoiesis. Int J Lab Hematol. 38(S1):20-6 (2016).
- Camaschella C. and Nai A., Ineffective erythropoiesis and regulation of iron status in iron-loading anemias. J. Haematol. 172(4):512-23 (2016)
- Silvestri L., Nai A., Pagani A. and Camaschella C. The extrahepatic role of TFR2 in iron homeostasis. Front Pharmacol. 5:93 (2014).
- Camaschella C., Nai A., Pagani A., Silvestri L. Matriptase-2, a novel suppressor of hepcidin. American Socierty of Hematology 2009, Program Book