Iron is a sensitive biomarker for inflammation in multiple sclerosis lesions
Veela Mehta, Wei Pei, Grant Yang, Suyang Li, Eashwar Swamy, Aaron Boster, Petra Schmalbrock, David Pitt, Veela Mehta, Wei Pei, Grant Yang, Suyang Li, Eashwar Swamy, Aaron Boster, Petra Schmalbrock, David Pitt
Abstract
MRI phase imaging in multiple sclerosis (MS) patients and in autopsy tissue have demonstrated the presence of iron depositions in white matter lesions. The accumulation of iron in some but not all lesions suggests a specific, potentially disease-relevant process, however; its pathophysiological significance remains unknown. Here, we explore the role of lesional iron in multiple sclerosis using multiple approaches: immunohistochemical examination of autoptic MS tissue, an in vitro model of iron-uptake in human cultured macrophages and ultra-highfield phase imaging of highly active and of secondary progressive MS patients. Using Perls' stain and immunohistochemistry, iron was detected in MS tissue sections predominantly in non-phagocytosing macrophages/microglia at the edge of established, demyelinated lesions. Moreover, iron-containing macrophages but not myelin-laden macrophages expressed markers of proinflammatory (M1) polarization. Similarly, in human macrophage cultures, iron was preferentially taken up by non-phagocytosing, M1-polarized macrophages and induced M1 (super) polarization. Iron uptake was minimal in myelin-laden macrophages and active myelin phagocytosis led to depletion of intracellular iron. Finally, we demonstrated in MS patients using GRE phase imaging with ultra-highfield MRI that phase hypointense lesions were significantly more prevalent in patients with active relapsing than with secondary progressive MS. Taken together, our data provide a basis to interpret iron-sensitive GRE phase imaging in MS patients: iron is present in non-phagocytosing, M1-polarized microglia/macrophages at the rim of chronic active white matter demyelinating lesions. Phase imaging may therefore visualize specific, chronic proinflammatory activity in established MS lesions and thus provide important clinical information on disease status and treatment efficacy in MS patients.
Conflict of interest statement
Competing Interests: DP has received funding from Five Prime, Biogen Idec, Novartis and Teva Pharmaceuticals for investigator-initiated trials. He also received consulting fees from Biogen Idec. AB has received research grants from Biogen Idec, Novartis, Actillion, Accorda and MerckSerono. He has also received consulting fees from Biogen Idec, Genzyme, Teva Neuroscience, Novartis, MerckSerono and Metronics. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
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Source: PubMed