Hemoglobin as a source of iron overload in multiple sclerosis: does multiple sclerosis share risk factors with vascular disorders?

Abstract

Although iron is known to be essential for the normal development and health of the central nervous system, abnormal iron deposits are found in and around multiple sclerosis (MS) lesions that themselves are closely associated with the cerebral vasculature. However, the origin of this excess iron is unknown, and it is not clear whether this is one of the primary causative events in the pathogenesis of MS, or simply another consequence of the long-lasting inflammatory conditions. Here, applying a systems biology approach, we propose an additional way for understanding the neurodegenerative component of the disease caused by chronic subclinical extravasation of hemoglobin, in combination with multiple other factors including, but not limited to, dysfunction of different cellular protective mechanisms against extracellular hemoglobin reactivity and oxidative stress. Moreover, such considerations could also shed light on and explain the higher susceptibility of MS patients to a wide range of cardiovascular disorders.

Fig. 1

Model illustrating how MS may be primarily caused by a cytodegenerative process aimed at the oligodendrocyte/myelin complex (adapted from Dr. Stys, Calgary [20]). Gradual demyelination and disruption can then lead to an autoimmune response and a cycle of further degeneration, characteristic of the most common relapsing-remitting manifestation of MS. Chronic demyelination results eventually in complete axonal degeneration

Fig. 2

Myelin damage by extravasation of erythrocytes and release of hemoglobin and heme: oxidative damage to lipids and proteins; membrane damage and cell death; inflammation and release of immunogenic peptides; protective mechanisms. BBB blood–brain barrier, RBC red blood cells, Hb hemoglobin, Hpt haptoglobin, Hpx hemopexin, HO heme-oxygenase, ROS reactive oxygen species. Hemin (ferric protoporphyrin IX) is the initial breakdown product of extracellular hemoglobin, and biliverdin, CO, and Fe²⁺ are the products of enzymatic (HO-1) heme catabolism