Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

Abstract

Background: 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.

Review: 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, since in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators. Some polyphenolic antioxidants may serve both roles.Understanding the exact speciation and liganding of iron in all its states is thus crucial to separating its various pro- and anti-inflammatory activities. Redox stress, innate immunity and pro- (and some anti-)inflammatory cytokines are linked in particular via signalling pathways involving NF-kappaB and p38, with the oxidative roles of iron here seemingly involved upstream of the IkappaB kinase (IKK) reaction. In a number of cases it is possible to identify mechanisms by which ROSs and poorly liganded iron act synergistically and autocatalytically, leading to 'runaway' reactions that are hard to control unless one tackles multiple sites of action simultaneously. Some molecules such as statins and erythropoietin, not traditionally associated with anti-inflammatory activity, do indeed have 'pleiotropic' anti-inflammatory effects that may be of benefit here.

Conclusion: Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time. Understanding these requires an integrative, systems-level approach that may lead to novel therapeutic targets.

Figure 1

An overview of this article, set out in the form of a 'mind map' [64].

Figure 2

Schematic overview of the main elements considered to participate in mammalian iron metabolism.

Figure 3

Some effects of hepcidin, summarizing the fact that hypoxic condition can suppress it and thus lead to hyperferraemia. Since hypoxic conditions can also lead to ROS production the hypoxia-mediated regulation of hepcidin can have especially damaging effects.

Figure 4

Overview of the roles of ischaemia, ROSs, poorly liganded iron and the iron metabolism regulators HGAL and hepicidin in effecting inflammation as a physiological level.

Figure 5

Role of inflammation caused by hydroxyl radical formation in the interactive development of obesity, the metabolic syndrome and diabetes. Intervention at multiple steps is likely to be most beneficial in alleviating this kind of progression.

Figure 6

Catalysis and autocatalysis in the Haber-Weiss and Fenton reactions leading to the production of the hydroxyl radical, including the liberation by superoxide of free iron from ferritin.

Figure 7

Some iron chelators that are in clinical use (left hand side) or that have been proposed.

Figure 8

An overview of cellular signaling using the NF-κB and p38 systems. Note that some of the extracellular effectors that mediate NF-κB activation are themselves produced and secreted as a result of the activation, potentially creating an autocatalytic system.

Figure 9

General view of the role of iron, antioxidants and ROSs in aging and degenerative processes. Some of the decay may be ameliorated by lifestyle and dietary means. Based in part on [1175].