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Published on: September 21, 2021
Iron deposition is independent of cellular inflammation in a cerebral model of multiple sclerosis
Rachel Williams1, Aaron M Rohr, Wen-Tung Wang
1Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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.
Insights
Iron deposits around blood vessels in the brain can occur without inflammation, challenging the hypothesis that iron causes inflammation in multiple sclerosis (MS). This study used a mouse model to investigate this relationship.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Multiple Sclerosis Pathogenesis
Background:
- Perivenular inflammation is a hallmark of early multiple sclerosis (MS).
- A hypothesis suggests CNS inflammation in MS is triggered by perivenular iron deposits linked to altered cerebral blood flow.
- A novel cerebral experimental autoimmune encephalomyelitis (cEAE) mouse model with perivascular iron deposits was developed to test this hypothesis.
Purpose of the Study:
- To investigate the relationship between iron deposition and inflammation in the central nervous system (CNS).
- To evaluate the hypothesis that perivenular iron deposits induce CNS inflammation in MS.
Main Methods:
- Cerebral experimental autoimmune encephalomyelitis (cEAE) was induced in mice.
- Cerebral blood flow was measured using Laser Doppler.
- Iron deposits, inflammation, microgliosis, and astrogliosis were assessed using MRI and histochemistry.
Main Results:
- cEAE mice exhibited reduced cerebral blood flow compared to controls.
- MRI showed T2 hypointense areas correlating with perivenular iron deposits in cEAE mice.
- Iron deposits were observed around vessels and within reactive microglia, but often without associated inflammatory cell infiltrates or astrogliosis.
Conclusions:
- Perivenular iron deposition can occur independently of inflammatory cell infiltrates.
- These findings do not support the hypothesis that iron deposits directly cause the inflammatory cell infiltrates seen in MS.
