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 1

Iron accumulates in subacute and chronic (but not acute) marmoset EAE lesions, inside microglia/macrophages, and in human MS lesions.

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Iron accumulates in subacute and chronic (but not acute) marmoset EAE le...
(A) In vivo MRI shows that once lesions are 6–8 weeks old, as determined by serial proton density-weighted (PDw) MRI (top row), they present a punctate hypointense signal on iron-sensitive T2*-weighted (T2*w) MRI (bottom row). (B) Intralesional hypointense signal on ex vivo T2*w MRI of the same lesion colocalizes with iron (DAB-Turnbull stain), as well as accumulation of microglia/macrophages (Iba1 immunohistochemistry) and demyelination (PLP immunohistochemistry). Note that the MRI section integrates over 100 μm of tissue and overemphasizes the extent of iron due to the “blooming artifact,” whereas the histopathological section is 5-μm thick, potentially accounting for apparent detailed discrepancies between the 2 images. (C) In vivo T2*-weighted MRI detects punctate hypointensity, suggesting iron deposition, in a representative white matter lesion in MS (red box). (D) Ex vivo T2*w MRI also detects intralesional hypointense foci in MS (red box). Histopathology confirms the presence of demyelination (PLP), as well as perivascular iron deposition (DAB-Turnbull), in MS, in a similar spatial pattern as observed in the marmoset EAE lesions. Scale bars: 100 μm for B, 20 μm for D. Counterstain: hematoxylin. Representative lesion from marmoset 1. Red box indicates magnified view on interpolated MRI.