Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis

Abstract

The role of activated microglia (MG) in demyelinating neurodegenerative diseases such as multiple sclerosis is controversial. Here we show that high, but not low, levels of IFN-g (a cytokine associated with inflammatory autoimmune diseases) conferred on rodent MG a phenotype that impeded oligodendrogenesis from adult neural stem/progenitor cells. IL-4 reversed the impediment, attenuated TNF-a production, and overcame blockage of IGF-I production caused by IFN-g. In rodents with acute or chronic EAE, injection of IL-4-activated MG into the cerebrospinal fluid resulted in increased oligodendrogenesis in the spinal cord and improved clinical symptoms. The newly formed oligodendrocytes were spatially associated with MG expressing MHC class II proteins and IGF-I. These results point to what we believe to be a novel role for MG in oligodendrogenesis from the endogenous stem cell pool. IntroductionRecovery from acute insults or chronic inflammatory and noninflammatory degenerative disorders in the CNS has been attributed to a limited capacity for neurogenesis and oligodendrogenesis, poor regeneration of injured nerves, and extreme vulnerability to degenerative conditions. Studies have demonstrated that the adult CNS contains stem cells that can give rise, albeit to a limited extent, both to neurons (1) and to oligodendrocytes (2) throughout life. Knowledge of the factors allowing such stem cells to exist, proliferate, and differentiate in the adult individual is a prerequisite for understanding and promoting the conditions conducive to CNS repair. This in turn can be expected to lead to the development of interventions aimed at boosting neural cell renewal from the endogenous stem cell pool or from exogenously applied stem cells.Studies have shown that inflammation within the CNS blocks neurogenesis (3, 4) and causes structural damage to myelin (5, 6). Moreover, "paralysis" of microglia (MG) and/or macrophages arrests progression of the transient monophasic disease EAE (7, 8). All of those findings were interpreted as evidence in support of the traditional view that the effect of local immune cells in the CNS is detrimental, and hence that recovery would require blockage, arrest, or elimination of local immune responses. Likewise, the limited regeneration and excessive vulnerability of CNS neurons under inflammatory conditions or after an acute insult were put down to the poor ability of the CNS to tolerate the immune-derived defensive activity that is often associated with local inflammation and cytotoxicity mediated, for example, by 9) or nitric oxide (10). More recent studies have shown, however, that although an uncontrolled local immune response indeed impairs

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

“…86 However, in the experimental allergic encephalomyelitis model, activated microglia could increase oligodendrogenesis. 87 The phenotypic heterogeneities in microglia may be related to the complex microglial roles on OPCs after brain injury. Pro-inflammatory (so-called M1-type) microglia dominantly exist in the early stage after demyelination and switch to anti-inflammatory or immunoregulatory (so-called M2-type) at the initiation of remyelination.…”

A Rose by Any Other Name? The Potential Consequences of Microglial Heterogeneity During CNS Health and Disease

“…16,17 Whether in vitro or in vivo, blocking neuronal activity with tetrodotoxin immediately leads to increased microglial expression of major histocompatibility complex (MHC) class II. 10,18,19 Healthy neurons express several molecules, such as CD200 and CD22, that actively downregulate microglial and macrophage activation state.…”

Immune Modulation in Glaucoma – Can Manipulation of Microglial Activation Help?

“…GA is a synthetic oligopeptide of four naturally occurring amino acids, its activity derives from its ability to serve as a "universal antigen' that weakly activates a wide spectrum of self-reactive T-cells (Kipnis and Schwartz, 2002). T-cell-based vaccination with GA resulted in decreased plaque formation, reduction of excitotoxicity and induction of neurogenesis in Alzheimer's disease (AD) mouse model (Butovsky et al, 2006a;2006b). This GA vaccination caused a phenotype switch in brain microglia to dendritic-like morphology, with the ability to produce insulin-like growth factor 1 (IGF-1) that counteracted the adverse Aβ-induced effects (Butovsky et al, 2006a;2006b;2007).…”

“…T-cell-based vaccination with GA resulted in decreased plaque formation, reduction of excitotoxicity and induction of neurogenesis in Alzheimer's disease (AD) mouse model (Butovsky et al, 2006a;2006b). This GA vaccination caused a phenotype switch in brain microglia to dendritic-like morphology, with the ability to produce insulin-like growth factor 1 (IGF-1) that counteracted the adverse Aβ-induced effects (Butovsky et al, 2006a;2006b;2007). Vaccination with GA significantly reduces loss of RGCs in rodent models of optic nerve crush injury, intraocular glutamate toxicity, glaucoma and macular degeneration (Schori et al, 2001).…”