The cytokines interleukin-6 and interferon-alpha induce distinct microglia phenotypes in the brain

Sustained production of high levels of interleukin (IL)-6 or interferon (IFN)-alpha in the central nervous system (CNS) is implicated in the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders and Aicardi-Goutières syndrome, respectively. Transgenic mice with CNS-targeted chronic production of IL-6 (GFAP-IL6) or IFN-alpha (GFAP-IFN) recapitulate important clinical and pathological features of these human diseases. The activation of microglia is a prominent manifestation found both in the human diseases and in the transgenic mice, yet little is known about how this contributes to disease pathology. Here we demonstrate that microglia show stimulus-specific responses to IL-6 versus IFN-alpha in the brain resulting in unique and extensive molecular and cellular adaptations. In GFAP-IL6 mice, microglia proliferated, had shortened, less branched processes and elicited transcriptomic and molecular changes associated with proliferation and phagocytosis. By contrast, microglia in the brain of GFAP-IFN mice exhibited increased proliferation and apoptosis, had larger, hyper ramified processes and showed transcriptomic and surface marker changes associated with antigen presentation and antiviral activity. Further, transcriptomic meta-analysis determined that in neurodegenerative and neuroinflammatory disorders, microglia exhibit IL-6- and IFN-alpha-like responses indicative of stronger, more extensive responses to these cytokines during autoimmunity and acute insult compared with neurodegenerative diseases. In conclusion, microglia responses to IL-6 and IFN-alpha are highly stimulus-specific, wide-ranging, give rise to divergent phenotypes and contribute to the phenotypes of these cells in human neurodegenerative diseases.