Transfer of Myelin-Reactive Th17 Cells Impairs Endogenous Remyelination in the Central Nervous System of Cuprizone-Fed Mice

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the CNS characterized by inflammation and neurodegeneration. Animal models that enable the study of remyelination in the context of ongoing inflammation are greatly needed for the development of novel therapies that target the pathological inhibitory cues inherent to the MS plaque microenvironment. We report the development of an innovative animal model combining cuprizone-mediated demyelination with transfer of myelin-reactive CD4 ϩ T cells. Characterization of this model reveals both Th1 and Th17 CD4 ϩ T cells infiltrate the CNS of cuprizone-fed mice, with infiltration of Th17 cells being more efficient. Infiltration correlates with impaired spontaneous remyelination as evidenced by myelin protein expression, immunostaining, and ultrastructural analysis. Electron microscopic analysis further reveals that demyelinated axons are preserved but reduced in caliber. Examination of the immune response contributing to impaired remyelination highlights a role for peripheral monocytes with an M1 phenotype. This study demonstrates the development of a novel animal model that recapitulates elements of the microenvironment of the MS plaque and reveals an important role for T cells and peripheral monocytes in impairing endogenous remyelination in vivo. This model could be useful for testing putative MS therapies designed to enhance remyelination in the setting of active inflammation, and may also facilitate modeling the pathophysiology of denuded axons, which has been a challenge in rodents because they typically remyelinate very quickly.

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

“…Furthermore, attenuation of brain T H 17 influx reduced white matter injury, limited brain atrophy, and prevented chronic functional deficits after neonatal hypoxia-ischemic injury [270]. These findings are in line with reports showing myelin-reactive T H 17 cells induced demyelination and impaired endogenous remyelination in pre-clinical white matter injury models and in multiple sclerosis patients [271–276]. In addition, curcumin, a curry spice that we found to improve TBI outcomes [243], attenuated expression of RORγT, a transcription factor involved in T H 17 differentiation, decreased myelin basic protein-autoreactive T cells, and blocked the production of IL-17, the signature cytokine released by T H 17 cells, after EAE [277].…”

Adaptive human immunity drives remyelination in a mouse model of demyelination

“…The injection of IL-4 treated MIGs in the CSF of EAE animal induced an increase of oligodendrogenesis in the spinal cord (Butovsky, 2006). In contrast, Th1 supernatants inhibit OPC differentiation in vitro (Moore et al , 2015) and transfer of enriched myelin-reactive Th17 cells impedes remyelination in a cuprizone model (Baxi et al , 2015). However, because cells were injected in the systemic compartment and not in the CNS parenchyma, the observed effects in the modulation of the remyelination process could be indirect.…”

Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases

“…In CX3CR1 deficient mice the clearance of myelin debris is abrogated, leading to improper remyelination [104]. A recent study demonstrated that myelin-reactive Th17 cells impair the endogenous remyelination process, possibly due to recruitment of pro-inflammatory peripheral monocytes [105]. Our unpublished data reveal that SOCS3 deficiency in myeloid cells results in a more severe and accelerated demyelination in response to cuprizone.…”