IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inﬂammation

Brain, 2016 · DOI: 10.1093/brain/aww254 · Published: October 25, 2016

Simple Explanation

Remyelination, the regeneration of the myelin sheath around nerve fibers in the central nervous system (CNS), often fails in progressive multiple sclerosis. This study investigates the role of interleukin-four induced one (IL4I1), an enzyme secreted by alternatively activated macrophages, in promoting remyelination and protecting axons. The research found that IL4I1 is upregulated during the resolution of inflammation and the onset of remyelination in mouse CNS lesions. Mice lacking IL4I1 showed impaired remyelination and increased axonal injury, while administration of recombinant IL4I1 enhanced remyelination and reduced pro-inflammatory macrophage density. Furthermore, IL4I1 modulates inflammation by reducing interferon gamma and IL17 expression in CNS tissues and activated T cells. Intravenous injection of IL4I1 in mice with experimental autoimmune encephalomyelitis (EAE) reversed disease severity, suggesting its potential as a therapeutic agent for promoting CNS repair in multiple sclerosis.

Study Duration

Not specified

Participants

Mice

Evidence Level

Not specified

Key Findings

1
IL4I1 is upregulated at the onset of inflammation resolution and remyelination in mouse central nervous system lesions.
2
IL4I1 modulates inflammation by reducing interferon gamma and IL17 expression in lesioned central nervous system tissues, and in activated T cells from splenocyte cultures.
3
Intravenous injection of IL4I1 into mice with experimental autoimmune encephalomyelitis at disease onset signiﬁcantly reversed disease severity, resulting in recovery from hindlimb paralysis.

Research Summary

This study demonstrates that IL4I1, an enzyme secreted by alternatively activated macrophages, plays a crucial role in augmenting CNS remyelination and axonal protection by modulating T cell-driven inflammation. IL4I1 expression is upregulated during inflammation resolution and remyelination, and its deficiency leads to impaired remyelination and increased axonal injury. Therapeutic administration of IL4I1 reverses disease severity in mice with EAE, suggesting its potential as a novel therapeutic target for promoting CNS repair in multiple sclerosis.

Practical Implications

Therapeutic Potential

IL4I1 shows promise as a novel therapeutic for promoting CNS repair and preventing disease progression in multiple sclerosis.

Inflammation Modulation

Modulating inflammation through IL4I1 could improve the environment in the CNS for remyelination.

T Cell Regulation

IL4I1's ability to regulate T cell expansion and activity could be harnessed to treat autoimmune diseases affecting the CNS.

Study Limitations

1
The exact mechanisms by which IL4I1 modulates inflammation in the demyelinated CNS remain unclear.
2
It is unknown if microglia-derived macrophages, monocyte-derived macrophages, or both are the source of IL4I1 in CNS lesions.
3
It remains to be determined if the effect of IL4I1 on inflammation in lysolecithin-demyelinated lesions and EAE are achieved through similar mechanisms.

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