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 September 9, 2019
Citation Information: J Clin Invest. 2019;129(10):4365-4376. https://doi.org/10.1172/JCI126809.
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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 6

Iron-regulating protein changes are cell-specific and dynamic in healthy white matter and lesions.

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Iron-regulating protein changes are cell-specific and dynamic in healthy...
(A) Panel of double stains (Iba1 for microglia/macrophages, together with the iron-regulating proteins transferrin receptor (TfR), ferroportin (FpN), and hepcidin (HpC)) in healthy white matter and various stages of marmoset EAE lesions. Microglia/macrophages weakly express all 3 iron-regulating proteins in healthy white matter. As lesions age, TfR and HpC levels increase, remaining high in chronically demyelinated (De) lesions but returning to baseline in remyelinated (Re) lesions. On the other hand, FpN levels slightly drop during demyelination but also return to normal upon remyelination. (B) Panel of double stains (GFAP for astrocytes, together with the same iron-regulating proteins). In the healthy white matter, astrocytes express TfR, which is lost upon demyelination but returns with remyelination. FpN and HpC levels increase in 2- to 6-week-old and chronically demyelinated lesions but also return to baseline with remyelination. (C) Panel of double stains (Olig2 for oligodendrocyte-lineage cells, likely a mixture of oligodendrocyte precursor cells and mature oligodendrocytes, together with iron-regulating proteins). In healthy white matter, TfR, FpN, and HpC are all expressed in the oligodendrocyte lineage (red arrows). In 2- to 6-week-old and chronically demyelinated lesions, oligodendrocyte-lineage cells are not detected. In repaired/remyelinated lesions, repopulated oligodendrocyte-lineage cells show all 3 proteins at relatively normal levels (red arrows). (D) Summary of iron regulation changes in microglia/macrophages and astrocytes during marmoset EAE lesion development and repair. Scale bars: 100 μm. Lesions selected from marmosets 1, 2, 6, 8, and 10.