Over the recent years, numerous studies have demonstrated the involvement of pro-inflammatory astrocyte-subsets in the pathogenesis and propagation of neuroinflammatory events, both in humans and animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. In this context, the continuous advent of single-cell methodologies has aided our understanding that these pathogenic and protective activation states expand or retract in a highly spatiotemporal-dependent manner. This becomes particularly important in stages of progressive neuroinflammation, when local inflammatory processes limit the regenerative capacity of CNS- resident glial cells, ultimately leading to clinical deterioration and chronification of disease. 

Here, we used CRISPR–Cas9-based genetic perturbation models, genome-wide analysis of DNA methylation in cortical astrocytes and novel treatment approaches combined with longitudinal Magnetic Resonance Imaging (MRI) to investigate the relevance of Heparin-binding EGF-like growth factor (HB-EGF) in the context of Experimental autoimmune encephalomyelitis (EAE), a preclinical mouse model of Multiple Sclerosis. 

We identify HB-EGF as part of a protective astrocyte activation state which limits late-stage CNS inflammation and is epigenetically silenced in progressive disease. Abrogation of astrocyte-derived HB-EGF resulted in impaired resolution of CNS inflammation and worsened progressive disease, concomitant with increased demyelination, neurodegeneration and persistent inflammation. In contrast, intranasal delivery of recombinant HB-EGF during acute and late-stage CNS inflammation attenuated disease severity, reduced lesion burden and facilitated recovery.

Overall, we demonstrate that chronic activation of astrocytes epigenetically suppresses protective HB-EGF signaling, and present novel strategies for the treatment of acute and chronic CNS inflammation.