Astrocytes fulfill multiple homeostatic and regulatory functions in healthy CNS. In MS, reactive astrocytes can enhance the pathological process by impairing blood brain barrier function, recruiting and activating lymphocytes, decreasing homeostatic functions and by adopting a neurotoxic phenotype.
We have shown that a genetic risk variant for MS susceptibility dysregulates astrocyte functions, leading to increased astrocyte-mediated neurotoxicity and more lymphocyte infiltration in MS lesion tissue. This suggests that genetic risk for MS is mediated not only by peripheral immune cells but in part also by astrocytes.
In addition, we have shown that MS progression is associated with increased adenosine A2A receptor expression in perilesional white matter, as measured by PET imaging. Moreover, we demonstrated that A2AR is expressed by two astrocyte phenotypes in MS lesion, characterized by pan-activation and by high oxidative damage. Finally, in human astrocyte cultures, A2AR signaling enhances oxidative damage in reactive human astrocytes. These findings indicate that A2AR signaling in specific astrocyte populations may drive oxidative damage which contributes to MS progression.
In addition to genetic risk variants, astrocyte function has been shown to be modified by environmental toxins and gut bacterial metabolites. Astrocyte-intrinsic pathways that are affected by modifiers may provide targets for treatment of relapsing-remitting and progressive MS.