CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

Abstract

A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology.

Chronic demyelination-induced seizures

“…Infiltration of microglia/macrophages peaks at 4.5 weeks of CPZ intoxication as is mediated by the chemokines CCL2, CCL3, and CXCL10 (Clarner et al, 2015). However, to the best of our knowledge, no studies have addressed microglia/macrophage behavior in the chronic CPZ model utilized in this study.…”

“…Glia were also assessed, since CPZ induces astrocytosis and phagocyte infiltration at intervals shorter than the chronic model utilized in this study (Norkute et al, 2008; Skripuletz et al, 2013; Gudi et al, 2014; Praet et al, 2014; Clarner et al, 2015). In addition, both human postmortem tissue and animal models of seizure show reactive astrocytes, which exhibit increased expression of the intermediate filament glial fibrillary acidic protein (GFAP) and alteration of astrocyte channels, including the water channel aquaporin-4 (AQP4) and the inward rectifying potassium channel Kir4.1, both of which are central to epileptogenesis (Oberheim et al, 2008; Anderson and Rodriguez, 2011; Binder et al, 2012; de Lanerolle et al, 2012; Rodriguez-Cruces and Concha, 2015; Nwaobi et al, 2016).…”

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

“…CXCL10 is a chemokine that can be produced by neurons, astrocytes, and oligodendrocytes (145) and binds the receptor CXCR3 on memory T cells and NK cells to induce their migration to the site of infection (146). Indeed, the NK-specific transcript, natural killer cell triggering receptor (NKTR), was upregulated 7 and 10 dpi (FC of 3 and 4, respectively).…”

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

“…Furthermore, activation of microglia and infiltration of macrophages into the brain are markedly increased during cuprizone intoxication (McMahon et al, 2002). Recently, it has been reported that microglial activation is significantly reduced in CXCL10-deficient mice treated with cuprizone, suggesting a pivotal role of CXCL10 in cuprizone-induced neuroinflammation and demyelination (Clarner et al, 2015). Similarly, IFN-g, IL-6, IL-8, CCL4, and CXCL10 were shown to be significantly increased in the CSF of ASD individuals (Vargas et al, 2005).…”