15 research outputs found
Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases
The production of peroxide and superoxide is an inevitable consequence of
aerobic metabolism, and while these particular "reactive oxygen species" (ROSs)
can exhibit a number of biological effects, they are not of themselves
excessively reactive and thus they are not especially damaging at physiological
concentrations. However, their reactions with poorly liganded iron species can
lead to the catalytic production of the very reactive and dangerous hydroxyl
radical, which is exceptionally damaging, and a major cause of chronic
inflammation. We review the considerable and wide-ranging evidence for the
involvement of this combination of (su)peroxide and poorly liganded iron in a
large number of physiological and indeed pathological processes and
inflammatory disorders, especially those involving the progressive degradation
of cellular and organismal performance. These diseases share a great many
similarities and thus might be considered to have a common cause (i.e.
iron-catalysed free radical and especially hydroxyl radical generation). The
studies reviewed include those focused on a series of cardiovascular, metabolic
and neurological diseases, where iron can be found at the sites of plaques and
lesions, as well as studies showing the significance of iron to aging and
longevity. The effective chelation of iron by natural or synthetic ligands is
thus of major physiological (and potentially therapeutic) importance. As
systems properties, we need to recognise that physiological observables have
multiple molecular causes, and studying them in isolation leads to inconsistent
patterns of apparent causality when it is the simultaneous combination of
multiple factors that is responsible. This explains, for instance, the
decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference
The role of activins in hepcidin regulation during malaria
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. 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-naïve 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 are unlikely to stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signalling 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
The role of activins in hepcidin regulation during malaria
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. 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-naïve 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 are unlikely to stimulate hepcidin
upregulation directly. In conclusion, we present evidence that the BMP/SMAD
signalling 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
Hepcidin deficiency and iron deficiency do not alter tuberculosis susceptibility in a murine M. tb infection model
Tuberculosis (TB), caused by the macrophage-tropic pathogen Mycobacterium tuberculosis (M.tb) is a highly prevalent infectious disease. Since an immune correlate of protection or effective vaccine have yet to be found, continued research into host-pathogen interactions is important. Previous literature reports links between host iron status and disease outcome for many infections, including TB. For some extracellular bacteria, the iron regulatory hormone hepcidin is essential for protection against infection. Here, we investigated hepcidin (encoded by Hamp1) in the context of murine M.tb infection. Female C57BL/6 mice were infected with M.tb Erdman via aerosol. Hepatic expression of iron-responsive genes was measured by qRT-PCR and bacterial burden determined in organ homogenates. We found that hepatic Hamp1 mRNA levels decreased post-infection, and correlated with a marker of BMP/SMAD signalling pathways. Next, we tested the effect of Hamp1 deletion, and low iron diets, on M.tb infection. Hamp1 knockout mice did not have a significantly altered M.tb mycobacterial load in either the lungs or spleen. Up to 10 weeks of dietary iron restriction did not robustly affect disease outcome despite causing iron deficiency anaemia. Taken together, our data indicate that unlike with many other infections, hepcidin is decreased following M.tb infection, and show that hepcidin ablation does not influence M.tb growth in vivo. Furthermore, because even severe iron deficiency did not affect M.tb mycobacterial load, we suggest that the mechanisms M.tb uses to scavenge iron from the host must be extremely efficient, and may therefore represent potential targets for drugs and vaccines
Dual RNA sequencing reveals dendritic cell reprogramming in response to typhoidal Salmonella invasion
Salmonella enterica represent a major disease burden worldwide. S. enterica serovar Typhi (S. Typhi) is responsible for potentially life-threatening Typhoid fever affecting 10.9 million people annually. While non-typhoidal Salmonella (NTS) serovars usually trigger self-limiting diarrhoea, invasive NTS bacteraemia is a growing public health challenge. Dendritic cells (DCs) are key professional antigen presenting cells of the human immune system. The ability of pathogenic bacteria to subvert DC functions and prevent T cell recognition contributes to their survival and dissemination within the host. Here, we adapted dual RNA-sequencing to define how different Salmonella pathovariants remodel their gene expression in tandem with that of infected DCs. We find DCs harness iron handling pathways to defend against invading Salmonellas, which S. Typhi is able to circumvent by mounting a robust response to nitrosative stress. In parallel, we uncover the alternative strategies invasive NTS employ to impair DC functions
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3
Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in iron deficiency (ID) and increased erythropoiesis but is pathologic in thalassaemia and haemochromatosis. Here we show that epigenetic events govern hepcidin expression. Erythropoiesis and ID suppress hepcidin via erythroferrone-dependent and -independent mechanisms respectively in vivo, but both involve reversible loss of H3K9ac and H3K4me3 at the hepcidin locus. In vitro, pan-histone deacetylase inhibition elevates hepcidin expression, and in vivo maintains H3K9ac at hepcidin-associated chromatin and abrogates hepcidin suppression by erythropoietin, ID, thalassaemia and haemochromatosis. HDAC3 and its cofactor NCOR1 regulate hepcidin; HDAC3 binds chromatin at the hepcidin locus, and HDAC3 knockdown counteracts hepcidin suppression induced either by erythroferrone or by inhibiting BMP signaling. In ID mice, the HDAC3 inhibitor RGFP966 increases hepcidin, and RNA-sequencing confirms hepcidin is one of the genes most differentially regulated by this drug in vivo. We conclude that suppression of hepcidin expression involves epigenetic regulation by HDAC3