Potential role of iron in repair of inflammatory demyelinating lesions
Nathanael J. Lee, … , Steven Jacobson, Daniel S. Reich
Nathanael J. Lee, … , Steven Jacobson, Daniel S. Reich
Published October 1, 2019; First published September 9, 2019
Citation Information: J Clin Invest. 2019;129(10):4365-4376. https://doi.org/10.1172/JCI126809.
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Categories: Research Article Neuroscience

Potential role of iron in repair of inflammatory demyelinating lesions

Abstract

Inflammatory destruction of iron-rich myelin is characteristic of multiple sclerosis (MS). Although iron is needed for oligodendrocytes to produce myelin during development, its deposition has also been linked to neurodegeneration and inflammation, including in MS. We report perivascular iron deposition in multiple sclerosis lesions that was mirrored in 72 lesions from 13 marmosets with experimental autoimmune encephalomyelitis. Iron accumulated mainly inside microglia/macrophages from 6 weeks after demyelination. Consistently, expression of transferrin receptor, the brain’s main iron-influx protein, increased as lesions aged. Iron was uncorrelated with inflammation and postdated initial demyelination, suggesting that iron is not directly pathogenic. Iron homeostasis was at least partially restored in remyelinated, but not persistently demyelinated, lesions. Taken together, our results suggest that iron accumulation in the weeks after inflammatory demyelination may contribute to lesion repair rather than inflammatory demyelination per se.

Authors

Nathanael J. Lee, Seung-Kwon Ha, Pascal Sati, Martina Absinta, Govind Nair, Nicholas J. Luciano, Emily C. Leibovitch, Cecil C. Yen, Tracey A. Rouault, Afonso C. Silva, Steven Jacobson, Daniel S. Reich

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Figure 7

Proposed model to explain perivascular iron deposition inside microglia/macrophages in marmoset EAE lesions.

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Proposed model to explain perivascular iron deposition inside microglia/...
Iron accumulates inside microglia/macrophages, which show increased expression of transferrin receptor (TfR), a main iron influx protein. Iron itself is transported across the endothelium of nearby blood vessels, which also upregulates TfR. Increased levels of hepcidin (HpC), which binds, internalizes, and degrades ferroportin (FpN), the main iron efflux channel protein, also contributes to intracellular iron accumulation. Iron regulation returns to homeostasis in remyelinated lesions, though iron levels within these cells remain high. Demyelinated lesions continue to show both dysregulated iron metabolism and persistent iron deposition. The source of iron observed in the oligodendrocyte-lineage cells of remyelinated lesions is not addressed by this study, but possible mechanisms include both direct transendothelial transport and release from microglia/macrophages.