Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions

Bogdan F Popescu,Graham N George,Susan Nehzati,Patrick D Fitz-Gibbon,Josa M Frischer,Simon Hametner,Stephen D Weigand,Samuel M Webb,Reginald C Adiele,Mylyne Tham,Ingrid J Pickering,Hans Lassmann,Wolfgang Brück,Christopher A Robinson,Imke Metz,Joseph E Parisi,Claudia F Lucchinetti,Guo Yong

doi:10.1007/s00401-017-1696-8

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.

Highlights

Multiple sclerosis (MS) is a central nervous system (CNS) chronic inflammatory demyelinating disease which targets oligodendrocytes and myelin
We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination
Using cutting edge synchrotron techniques that are sensitive and specific to detect metals [52], we report for the first time that astrocytes in large astrogliotic regions in a subset of smoldering and inactive plaques accumulate iron, and safely store it as ferrihydrite in ferritin

Summary

Introduction

Multiple sclerosis (MS) is a central nervous system (CNS) chronic inflammatory demyelinating disease which targets oligodendrocytes and myelin. X-ray fluorescence imaging (XFI) is elementspecific, quantitatively detects all chemical forms of any metal and simultaneously maps multiple metals, addressing the limitations of histochemistry [45, 46, 48, 49, 52]. This is the first systematic synchrotron X-ray fluorescence study to compare the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing white matter (normal appearing WM) and periplaque white matter (periplaque WM) from a given patient, and to assess the involvement of these metals in MS lesion pathogenesis.

Results

Discussion

Conclusion

Compliance with ethical standards