Identification of a microglia phenotype supportive of remyelination

Abstract

In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelinationsupportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. V

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

“…In this model, the vast majority of activated MPs are endogenous microglia, not peripheral macrophages (49)(50)(51)(52). At W4 of CPZ, proinflammatory MPs in the corpus callosum express the phagocytic marker CD11b and are responsible for the phagocytosis of myelin debris (53,54). This supportive action of MPs is an essential step for subsequent remyelination at W6 and W6 + W6 recovery (49,55).…”

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells

“…This is achieved by removing myelin debris, thus permitting entry of oligodendrocyte precursor cells. Phagocytosing myeloid cells are also implicated as sources of molecular signals that attract and support the differentiation of the oligodendrocyte precursor cells (45,46). Understanding and potentially manipulating the phagocytic clearance of myelin has clear consequences for MS.…”

IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

“…Furthermore, myelin debris may contain inhibitory molecules that antagonize axonal regeneration (45), and the removal of axonal debris by microglia increases axonal regeneration (46,47). Additionally, microglial phagocytosis of myelin debris can promote resolution of the CNS inflammatory response (16,48), and myelin-phagocytosing microglia express genes involved in the activation, migration, proliferation, and differentiation of oligodendrocyte precursor cells (49). Recently, it has been shown that if CNS-resident microglia cannot clear degenerated myelin from affected axons, remyelination is impaired, whereas infiltrating macrophages did not contribute to this function (50).…”