IL4I1 decreases inflammation and promotes CNS repair in models of multiple sclerosis

Written by Kerstetter-Fogle A

Evaluation of: Psachoulia K, Chamberlain KA, Heo D et al. IL4I1 augments CNS remyelination and axonal protection by modulating T-cell driven inflammation. Brain 139(Pt 12), 3121–3136 (2016).
Multiple sclerosis (MS) is a highly complex disease involving inflammation, demyelination and spontaneous demyelination–remyelination episodes which ultimately fail during the course of the disease. The prognosis for patients is often bleak. Molecular evidence has demonstrated that activated inflammatory mediators are important for the differentiation of oligodendrocyte progenitors into functional myelin. In the paper published in Brain under discussion, the researchers categorized the role of alternatively activated macrophages (AAM) versus classically activated macrophages (CAM) as being beneficial for the promotion of remyelination. There is distinct temporal activation of macrophages within lesions of the CNS. During CNS remyelination and tissue repair processes, inflammatory processes are tightly regulated. IL4I1 is highly expressed during CNS remyelination. IL4I1 is expressed by immune cells, is stimulated by IL-4 and has immunomodulatory functions in various tumors and bacterial infections. The authors set out to determine whether IL4I1 affects remyelination or protects axonal damage in a mouse model of MS. 
Initial studies in this area looked at transcriptome analysis of microdissected rat CNS lesions and found IL4I1 to be associated and upregulated with CNS remyelination at 14 days post-lesion, which is when inflammation is typically resolved and spontaneous remyelination begins to occur. Lysolecithin focal lesions were then performed in a mouse model and characterized. Oligodendrocyte precursor cell recruitment occurred at 3 days post-lesion and differentiation occurred at 10 days post-lesion. Completion of remyelination was at 20 days post-lesion. Interestingly, polymerase chain reaction analysis determined IL4I1 expression was induced at 10 days, post-lesion, and decreased by 20 days, after lesion. In situ hybridization determined that IL4I1 was detected in cells resembling macrophages. To determine the signaling in macrophages, they induced primary microglia and macrophage cell lines with IL4 and found that IL4I1 expression was increased. In their IL4 knockout mouse model of demyelination, IL4I1 was reduced as compared with wild type. So IL4I1 is dependent on IL4 receptor activation and is important in AAM. Addition of IL4I1 to oligodendrocyte lineage cells did not affect the number of precursors or oligodendrocytes so it is not a direct link between IL4I1 and maturation.

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