Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention

Abstract

The redox properties that make iron an essential nutrient also make iron an efficient pro-oxidant. Given this nascent cytotoxicity, iron homeostasis relies on a combination of iron transporters, chaperones, and redox buffers to manage the non-physiologic aqueous chemistry of this first-row transition metal. Although a mechanistic understanding of the link between brain iron accumulation (BIA) and neurodegenerative diseases is lacking, BIA is co-morbid with the majority of cognitive and motor function disorders. The most prevalent neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple System Atrophy (MSA), and Multiple Sclerosis (MS), often present with increased deposition of iron into the brain. In addition, ataxias that are linked to mutations in mitochondrial-localized proteins (Friedreich's Ataxia, Spinocerebellar Ataxias) result in mitochondrial iron accumulation and degradation of proton-coupled ATP production leading to neuronal degeneration. A comorbidity common in the elderly is a chronic systemic inflammation mediated by primary cytokines released by macrophages, and acute phase proteins (APPs) released subsequently from the liver. Abluminal inflammation in the brain is found downstream as a result of activation of astrocytes and microglia. Reasonably, the iron that accumulates in the brain comes from the cerebral vasculature via the microvascular capillary endothelial cells whose tight junctions represent the blood-brain barrier. A premise amenable to experimental interrogation is that inflammatory stress alters both the trans- and para-cellular flux of iron at this barrier resulting in a net accumulation of abluminal iron over time. This review will summarize the evidence that lends support to this premise; indicate the mechanisms that merit delineation; and highlight possible therapeutic interventions based on this model.

Keywords: aging; blood-brain barrier; brain iron; chronic inflammation; iron trafficking; neurodegeneration.

Figure 1

Methods of iron trafficking in BMVECs. This image highlights the uptake and efflux pathways used for iron transport in BMVECs. The yellow bars represent tight junctions which will be discussed in a later section. ZIP8/14 can transport transferrin bound iron (TBI) and non-transferrin bound iron (NTBI), with the help of a reductase which reduces the iron and allows it to enter the cell. Ferric (Fe³⁺) iron binds to transferrin, creating holo-Tf which binds to TfR and is endocytosed into an endolysosome in the cell. Here, the iron is reduced and leaves the endolysosome through DMT1. Within the cell, ferrous iron (Fe²⁺) can be stored in ferritin for later use. When the iron is ready to exit the cell, it is first oxidized back to ferric iron by a ferroxidase, and exits through ferroportin (FPN). Hepcidin is an effector hormone known to induce degradation of ferroportin and prevent cellular iron efflux. This image was created with Biorender.com.

Figure 2

Acute phase response effect on cellular iron trafficking. Essentially all of the cytokines released upon activation of macrophages and monocytes trigger changes in most if not all tissues with impact on their iron trafficking. In addition, several of the acute phase proteins released from hepatocytes (APP) have a sustaining effect on these processes. Hepcidin (Hepc) has the specific role of modulating the steady-state level of the sole iron efflux transporter, Ferroportin (FPN), in a cell's plasma membrane, thus regulating cell iron efflux. This image was created with Biorender.com.

Figure 3

Mechanisms for brain iron accumulation in a state of chronic inflammation. In a state of chronic inflammation, systemic inflammatory factors increase plasma membrane iron transporter occupancy. These include the ferrous iron uptake transporters, ZIP8 and ZIP14, and the sole iron efflux transporter Fpn. Note that these changes occur at both the apical (blood) and basolateral (brain) side of the endothelial cell blood-brain barrier in response to systemic and abluminal signals. This image was created with Biorender.com.

Figure 4

Endothelial junctions at the Blood Brain Barrier. Illustration depicting tight junctions and adherens junctions in brain microvascular endothelial cells of the BBB. Inducers of BBB breakdown are shown both in the systemic circulation and brain interstitium. TJ and AJ proteins are depicted between the two endothelial cells. Inducers shown on either side of the BBB make modifications such as phosphorylation, or glutathionylation, that have downstream effects on TJ/AJ localization and expression. This alters BBB integrity and barrier leakiness. This image was created with Biorender.com.