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Hepcidin and Trypanosoma brucei infection
leading to a recovery from anemia. No significant changes were observed in duodenal levels of ferroportin. It is likely that body iron levels were already sufficient to cope with the erythropoietic demands, so there was no need for additional dietary iron absorption. Additionally, we must also consider that analysis of ferroportin by Western blot does not distinguish between functional ferroportin on the cell membrane and possibly non-functional ferroportin in intracellular compartments, which could hide the smaller differences between WT and KO mice. Nevertheless, it is clear that the lack of hepcidin allows for a faster recovery and normalization of ferroportin levels, and thus, for an earlier availability of iron required for erythropoiesis.
The later suppression of hepcidin also negatively corre- lates with increases in the expression of several erythroid regulators. Erythropoietin (EPO) is one of the signaling molecules driving erythropoiesis, being produced mostly by the kidney. It is essential for EPO receptor (R)-mediated erythropoiesis that occurs in the BM and the spleen. Although EPO can influence hepcidin expression, it does not seem to act directly on it, but rather indirectly through erythroferrone (ERFE) produced by erythroid progeni- tors.57 Interestingly, there is no major role for ERFE in base- line erythropoiesis, but it rather functions during erythro- poiesis-related stress58 and during recovery from anemia of inflammation,59 by suppressing hepcidin and increasing iron availability. Our data show that in Hamp-/- mice ERFE does not seem to be involved in the recovery from ane- mia, despite the increase in EPO, since no variations in expression were observed, which opens up the possibility that ERFE is not only involved in hepcidin suppression, but also acts as a sensor for hepcidin levels. Other ery- throid regulators that can influence hepcidin, such as the predominantly erythroblast-produced GDF15 and TWSG1,60,61 were also found to be over-expressed at the later stage of infection and could contribute to hepcidin suppression. These findings are very similar to previous observations in bacterial infections. During injection with heat-inactivated Brucella abortus,25,26 C57BL/6 mice have similar patterns of hepcidin expression, with a significant increase in the early days and a decrease in later days of infection. Mice also develop anemia of inflammation and iron restriction, and can only partially recover from it. However, when hepcidin is suppressed (in Hamp-/- mice), anemia is ameliorated and there is a faster recovery.
Furthermore, a role for IL-6 in the onset and resolution of anemia is also shown,26 both by triggering increased hep- cidin expression and by interfering with erythropoiesis. However, recovery from anemia in IL-6-/- mice is not as fast as in Hamp-/- mice, showing that although IL-6 is a strong inducer of hepcidin during inflammatory condi- tions, it is not the only one.
In summary, T.b. brucei infection leads to the rapid devel- opment of anemia followed by a partial recovery (Figure 8). In the acute phase, a strong inflammatory signature is associated with hepcidin expression causing iron redistri- bution and limited availability. During the recovery phase, the decrease in hepcidin expression might be due to the decrease in the inflammatory response and the increased production of erythroid regulators. Importantly, the lack of hepcidin clearly reduces the severity of trypanosome- derived anemia. This knowledge could contribute to the development of novel strategies for the treatment and control of trypanosomiasis-derived anemia, limiting its impact on human and non-human health.
Disclosures
This work is a result of the project Norte-01-0145-FEDER- 000012 - Structured Program on Bioengineered Therapies for Infectious Diseases and Tissue Regeneration, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and by individual funding from the Portuguese Foundation for Science and Technology (FCT) through CEECIND/00048/2017 (ACG), SFRH/BD/114899/2016 (CB), SFRH/BD/ CEECIND/02362/2017 (JT), SFRH/BD/123734/2016 (DMC).
Contributions
JVN, ACG, DMC and CB performed research; JVN, ACG and DMC performed data analysis; JVN, ACG and DMC wrote the manuscript; JVN, JT, ACS and PNSR supervised the study; SV provided the Hamp KO animals; PNSR, JT, ACS, SV contributed data and edited the manuscript. All authors revised and approved the manuscript.
Acknowledgments
GVR35 line expressing the red-shifted luciferase was kindly provided by Prof. Jeremy Mottram, University of York, UK.
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