IL-10 signaling regulates lesion expansion during viral demyelination
Ángel L. Reyes-Rodríguez, Ph.D.1, Alice Valentín-Torres, Ph.D.2, Alberto Williams-Medina3, Carine Savarin, Ph.D.1, Shweta Puntambekar, Ph.D.4, and Cornelia Bergmann, Ph.D.1
1Department of Neurosciences, Neuroinflammation Research Center, Cleveland Clinic, Cleveland, OH; 2Department of Regenerative Medicine, Athersys, Cleveland, OH; 3College of Sciences and Health Professions, Cleveland State University, Cleveland, OH
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that limits both T cell function and immunopathology. Following encephalomyelitis induced by the glia-tropic murine hepatitis virus MHV-JHM strain, antiviral T cells control infectious virus, but viral RNA persists at low levels in spinal cords. T cell mediated viral control is associated with ongoing primary demyelination throughout persistence. In the absence of IL-10, virus control is accelerated, but viral RNA persists at similar levels. Further, although myelin loss is initially reduced, demyelination increases throughout persistence in IL-10 deficient mice. Moreover, increased lesion size is associated with more activated microglia/macrophages and reduced astroglia mesh formation within lesions. In an effort to characterize the responder cells responsible for IL-10 mediated lesion containment, we monitored IL-10 receptor (IL-10Ra) expression. In naïve mice, microglia and monocytes, but not astrocytes, express readily detectable IL-10Ra. However, while IL-10Ra is progressively downregulated in microglia and infiltrating macrophages during infection, it is strongly upregulated in astrocytes. Infection of mice with abrogated IL-10 signaling in monocytes/macrophages (LysMcre+ IL-10Rafl/fl) showed no differences in viral control, but exhibited increased lesion size during persistence. Similar to total IL-10 deficient mice, lesions in LysMcre+ IL-10Rafl/fl mice also showed increased activation of Iba-1+ cells, elevated iNOS and sustained class II expression, compared to their LysMcre- littermates. While astrocytes within lesions showed morphologies similar to wild type mice, they displayed an 'invasive' morphology at lesions borders. Together, these data support that IL-10 signaling to macrophages plays a role in restricting lesion size by diminishing their pro-inflammatory profile, but also affecting astrocyte protective functions.