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Open Access Highly Accessed Research article

Iron deposition is independent of cellular inflammation in a cerebral model of multiple sclerosis

Rachel Williams1, Aaron M Rohr1, Wen-Tung Wang2, In-Young Choi124, Phil Lee12, Nancy EJ Berman3, Sharon G Lynch4 and Steven M LeVine1*

Author affiliations

1 Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160

2 Hoglund Brain Imaging Center, University of Kansas Medical Center, Kansas City, KS 66160

3 Department of Anatomy & Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160

4 Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160

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Citation and License

BMC Neuroscience 2011, 12:59  doi:10.1186/1471-2202-12-59

Published: 23 June 2011

Abstract

Background

Perivenular inflammation is a common early pathological feature in multiple sclerosis (MS). A recent hypothesis stated that CNS inflammation is induced by perivenular iron deposits that occur in response to altered blood flow in MS subjects. In order to evaluate this hypothesis, an animal model was developed, called cerebral experimental autoimmune encephalomyelitis (cEAE), which presents with CNS perivascular iron deposits. This model was used to investigate the relationship of iron deposition to inflammation.

Methods

In order to generate cEAE, mice were given an encephalitogen injection followed by a stereotactic intracerebral injection of TNF-α and IFN-γ. Control animals received encephalitogen followed by an intracerebral injection of saline, or no encephalitogen plus an intracerebral injection of saline or cytokines. Laser Doppler was used to measure cerebral blood flow. MRI and iron histochemistry were used to localize iron deposits. Additional histological procedures were used to localize inflammatory cell infiltrates, microgliosis and astrogliosis.

Results

Doppler analysis revealed that cEAE mice had a reduction in cerebral blood flow compared to controls. MRI revealed T2 hypointense areas in cEAE animals that spatially correlated with iron deposition around vessels and at some sites of inflammation as detected by iron histochemistry. Vessels with associated iron deposits were distributed across both hemispheres. Mice with cEAE had more iron-labeled vessels compared to controls, but these vessels were not commonly associated with inflammatory cell infiltrates. Some iron-laden vessels had associated microgliosis that was above the background microglial response, and iron deposits were observed within reactive microglia. Vessels with associated astrogliosis were more commonly observed without colocalization of iron deposits.

Conclusion

The findings indicate that iron deposition around vessels can occur independently of inflammation providing evidence against the hypothesis that iron deposits account for inflammatory cell infiltrates observed in MS.