Defective Microglia-Neuronal Communication during Demyelinating Disease Correlates with Altered Neurogenesis

Abstract

Abstract Inflammatory demyelination is a hallmark of the pathology of multiple sclerosis (MS) and microglia are considered responsible for exacerbating myelin loss. The link between inflammation and neural stem cell (NSC) development, key events during the remyelination process, is being increasingly recognized. However, the mechanisms that connect microglia, myelination and inflammatory-mediated oxidative damage are unclear. Fractalkine (FKN), a neuronal derived chemokine, and its unique receptor, CX3CR1, expressed by microglia, are highly abundant in the healthy brain, and our laboratory has reported severe CNS demyelination and neuronal damage in EAE-induced CX3CR1-KO mice. Our hypothesis is that CX3CR1-defective signaling promotes inflammatory-mediated damage to neuron and myelin-forming cells. We found that expression of the adhesive defective human variant hCX3CR1-M280 caused enhanced disease severity, increased demyelination and exacerbated neuronal loss, mirroring the findings we observed in CX3CR1KO mice. Also, enhanced demyelination was observed after 4 wk of cuprizone treatment. Densities of NG2+ glia were comparable between WT and CX3CR1KO mice, but a significant reduction in DCX+ cells in the subgranular zone of the hippocampus was observed. In addition, lipocalin-2 an acute phase protein, linked to resolution of inflammation by reducing iron-induced toxicity, was found upregulated in cuprizone-induced demyelinated lesions of WT but not CX3CR1KO or hCX3CR1M280 mice. Thus, the FKN/CX3CR1 signaling pathway in microglia plays an under-appreciated role in MS, perhaps via anti-inflammatory processes that enhance neurogenesis through regulation of oxidative damage.