Role of Activins in Hepcidin Regulation during Malaria.

Natasha Spottiswoode,Hal Drakesmith,Andrew E Armitage,Prateek Choudhary,Susanne H Hodgson,Simon J Draper,Alex J Fyfe,Patrick E Duffy,Andrew R Williams,Sumi Biswas,David Llewellyn,John H Adams

doi:10.1128/iai.00191-17

Abstract

ABSTRACTEpidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life-threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in Plasmodium berghei murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway target genes, a key pathway involved in hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD pathway and found that Bmp gene expression was not increased in infection. In contrast, activin B, which can signal through the BMP/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of Plasmodium berghei-infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Plasmodium chabaudi. Concentrations of the closely related protein activin A increased in parallel with hepcidin in serum from malaria-naive volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins do not stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signaling pathway is perturbed in malaria infection but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting.

Highlights

Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life-threatening anemia that may accompany blood-stage malaria infection
We find evidence that the bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway is involved in hepcidin upregulation but that activin B and activin A are increased in malaria, these molecules are unlikely to play a major role in controlling hepcidin expression
Hepcidin upregulation during murine Plasmodium berghei infection is associated with increased BMP/SMAD pathway activity

Summary

Introduction

Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life-threatening anemia that may accompany blood-stage malaria infection. We present evidence that the BMP/SMAD signaling pathway is perturbed in malaria infection but that activins, raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting. Hepcidin levels increase homeostatically under high-iron conditions [7] and in response to inflammation and infection [25] via the BMP/SMAD and interleukin-6 (IL-6)/STAT3 pathways, respectively. Appropriate regulation of hepcidin levels in response to fluctuations in iron is complex and requires many proteins, including Bmp, HJV, Bmp type I and type II receptors, Hfe, and TfR2. These molecules combine to sense iron and to modulate transcription of hepcidin via the BMP/SMAD signaling pathway [26]. A recently identified bone marrow-derived erythropoietin-induced hormone named erythroferrone likely plays a key role in hepcidin suppression in this context [27], which appears to act via BMP/SMAD signaling [28]

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Results

Conclusion