Page 160 - 2021_03-Haematologica-web

Ferrata Storti Foundation
Haematologica 2021 Volume 106(3):806-818
Iron Metabolism and its Disorders
A role for hepcidin in the anemia caused by Trypanosoma brucei infection
João V. Neves,1,2,3 Ana C. Gomes,1,2,3 David M. Costa,1,4 Carolina Barroso,1,2,5 Sophie Vaulont,6 Anabela Cordeiro da Silva,1,3,4 Joana Tavares1,4 and Pedro N.S. Rodrigues1,2,3
1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; 2Iron and Innate Immunity, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; 3ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal; 4Parasite Disease, IBMC – Instituto de
5
Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; MCBiology
Doctoral Program, ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal and 6INSERM U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
ABSTRACT
Trypanosomiasis is a parasitic disease affecting both humans and ani- mals in the form of Human African Trypanosomiasis and Nagana dis- ease, respectively. Anemia is one of the most common symptoms of trypanosomiasis, and if left unchecked can cause severe complications and even death. Several factors have been associated with the development of this anemia, including dysregulation of iron homeostasis, but little is known about the molecular mechanisms involved. Here, using murine models, we study the involvement of hepcidin, the key regulator of iron metabolism and an important player in the development of anemia of inflammation. Our data show two stages for the progression of anemia, to which hepcidin con- tributes a first stage when anemia develops, with a likely cytokine-mediated stimulation of hepcidin and subsequent limitation in iron availability and erythropoiesis, and a second stage of recovery, where the increase in hep- cidin then declines due to the reduced inflammatory signal and increased production of erythroid regulators by the kidney, spleen and bone marrow, thus leading to an increase in iron release and availability, and enhanced ery- thropoiesis. In agreement with this, in hepcidin knockout mice, anemia is much milder and its recovery is complete, in contrast to wild-type animals which have not fully recovered from anemia after 21 days. Besides all other factors known to be involved in the development of anemia during try- panosomiasis, hepcidin clearly makes an important contribution to both its development and recovery.
Introduction
African trypanosomes are extracellular protozoan parasites transmitted by the hematophagous tsetse fly (Glossina spp), and are responsible for debilitating med- ical and veterinary diseases in sub-Saharan Africa.1 Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense infect humans and are responsible for the fatal Human African Trypanosomiasis, also known as sleeping sickness.2 Trypanosoma brucei brucei is responsible for animal trypanosomiasis, which mostly affects cattle.2
One of the most common complications of trypanosomiasis is anemia, both in humans and animals,3-5 which in conjunction with other symptoms can be a major cause of death if left untreated, particularly in livestock.6 Over the years, several causes for this anemia have been described, and these include both parasite and host-associated factors.7-9 Erythrophagocytosis by activated liver and spleen myeloid cells has been identified as a major contributor to erythrocyte clearance. In addition, the lipid composition of erythrocytes is altered during trypanosome infec- tion and these are preferentially phagocytosed.8
Among the parasite factors that contribute to anemia are the expression of extra-
Correspondence:
JOÃO V. NEVES
jneves@ibmc.up.pt
Received: May 30, 2019. Accepted: January 2, 2020. Pre-published: January 9, 2020.
https://doi.org/10.3324/haematol.2019.227728
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
806
haematologica | 2021; 106(3)
ARTICLE