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

Steven M Levine,In-Young Choi,Nancy Ej Berman,Phil Lee,Sharon G Lynch,Aaron M Rohr,Rachel Williams,Wen-Tung Wang

doi:10.1186/1471-2202-12-59

Steven M Levine, In-Young Choi + Show 6 more

Open Access

https://doi.org/10.1186/1471-2202-12-59

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Abstract

BackgroundPerivenular 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.MethodsIn 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.ResultsDoppler 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.ConclusionThe 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.

Highlights

Perivenular inflammation is a common early pathological feature in multiple sclerosis (MS)
Female SJL mice were anesthetized with avertin and given a total dose of 75 μg proteolipid protein (PLP) peptide with 150 μg M. tuberculosis that was divided into 3 s.c. injections on the dorsum
Iron deposits were observed within inflammatory cells in the subcortical white matter (Figure 1), lining blood vessels in the cortex (Figures 1, 2), dispersed in the neuropil, and in cells surrounding the vessels (Figure 2B) in both hemispheres

Summary

Introduction

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. Recent studies suggest a possible link between iron deposition around vessels, poor venular blood flow and perivascular inflammation in the CNS of multiple sclerosis (MS) subjects [1,2,3,4]. Inflammatory cell infiltrates located around CNS veins are a recurring pathological characteristic observed in MS, relapsing remitting MS [12,15,16] Despite these observations it is unknown whether iron deposition, reduced blood flow, and perivascular inflammation are interrelated.

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