Microglial Recruitment, Activation, and Proliferation in Response to Primary Demyelination

Abstract

We have characterized the cellular response to demyelination/remyelination in the central nervous system using the toxin cuprizone, which causes reproducible demyelination in the corpus callosum. Microglia were distinguished from macrophages by relative CD45 expression (CD45 dim ) using flow cytometry. Their expansion occurred rapidly and substantially outnumbered infiltrating macrophages and T cells throughout the course of cuprizone treatment. We used bromodeoxyuridine incorporation and bone marrow chimeras to show that both proliferation and immigration from blood accounted for increased microglial numbers. Microglia adopted an activated phenotype during demyelination, up-regulating major histocompatibility class I and B7.2/CD86. A subpopulation of CD45 dim-high microglia that expressed reduced levels of CD11b emerged during demyelination. These microglia expressed CD11c and were potent antigen-presenting cells in vitro. T cells were recruited to the demyelinated corpus callosum but did not appear to be activated. Our study highlights the role of microglia as a heterogeneous population of cells in primary demyelination, with the capacity to present antigen, proliferate, and migrate into demyelinated areas.

Both TLR2 and TLR4 Are Required for the Effective Immune Response in Staphylococcus aureus-Induced Experimental Murine Brain Abscess

“…Expansion of microglia has also been shown after cuprizone treatment and in response to transsection of axons in the entorhinal cortex by several investigators. 43,[57][58][59] In contrast to these "noninfectious " models, in which lesion-induced microglial proliferation was reduced in TLR2 Ϫ/Ϫ mice in the early phase, 43 a prominent activation of microglial cells was remarkable in TLR2 Ϫ/Ϫ mice until late stages of brain abscess, which may also be fostered by high levels of chemokines like CCL2 during the later course of the disease.…”

Identification of a microglia phenotype supportive of remyelination

“…We used the cuprizone model in which the uncompromised blood-brain barrier (Bakker and Ludwin, 1987;Kondo et al, 1987;McMahon et al, 2002) and the lack of infiltrating peripheral immune cells (McMahon et al, 2002;Remington et al, 2007) allow detailed study of the microglia phenotype associated with demyelination and remyelination. Moreover, demyelination and remyelination in the cuprizone model follow a highly reproducible time course (Gudi et al, 2009;Matsushima and Morell, 2002), making it technically feasible to experimentally dissect the two processes and the related microglia phenotype changes.…”

“…In this model, primary demyelination and the subsequent remyelination occur with minimal contribution from peripheral immune cells (Matsushima and Morrel, 2002;McMahon et al, 2002;Remington et al, 2007), allowing us to characterize the role of microglia independently of the peripheral immunity.…”

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).…”