Abstract
A pathological hallmark of multiple sclerosis (MS) is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in MS, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS)
Tamoxifen-induced conditional deletion of the macrophage colony-stimulating factor (mCSF) receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes
Wild type mice were fed with normal chow or cuprizonesupplemented chow during 5 weeks, as the peak of demyelination occurs between 4 weeks and 5 weeks of diet
Summary
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS). Remyelination that counteracts myelin loss and prevents degeneration of the denuded axons is often compromised in chronically demyelinated lesions. While a number of publications points towards a noxious role of innate immune cells in MS considering their antigen-presenting nature and ability to release pro-inflammatory cytokines, which may directly affect the myelin sheaths, others emphasize their beneficial roles in disease progression (Cash et al, 1993; Rawji and Yong, 2013; McMurran et al, 2016). A growing body of evidence demonstrates that microglia, the resident innate immune cells of the brain, have regenerative properties, releasing growth factors and phagocytosing myelin debris during the demyelination phase (Miron et al, 2013; Rawji and Yong, 2013; Fu et al, 2014). A tight balance between boosting remyelination while limiting demyelination needs to be achieved through the modulation of oligodendrocyte survival, differentiation and proliferation, as well as microglial activity
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