Role of the Complement System in Cytokine-driven Neuroinflammation

Abstract

The cytokines interleukin-6 (IL-6) and interferon alpha (IFN-a) are vital mediators of innate immunity. However, chronic overproduction of IL-6 or IFN-a in the central nervous system (CNS) can cause neuromyelitis optica spectrum disorders (NMOSD) and Aicardi-Goutières syndrome (AGS), respectively. In NMOSD and AGS, dysregulation of the complement system (CS) also plays a pathogenic role. The CS is an indispensable effector of innate immunity, working to opsonise pathogens, instigate inflammation, and lyse cells. IL-6, IFN-a, and various CS factors can regulate the production of one another under certain conditions. Thus, the focus of the present study was to determine whether certain CS factors mediate cytokine-driven disease. To answer this question, we utilised two transgenic mouse lines with CNS-restricted, chronic overexpression of IL-6 (GFAP-IL6 mice) or IFN-a (GFAP-IFN mice), that recapitulate many features of cytokine-driven disease in humans. We first explored the transcriptomic profile of these mouse lines to determine if CS components were dysregulated. We then chronically treated GFAP-IL6 and GFAP-IFN mice with a complement C5aR1 antagonist to explore the effect of C5aR1 inhibition on cytokine-driven disease progression, and whether complement manipulation is a therapeutic avenue for IL-6 and IFN-a mediated disorders. In the CNS of both GFAP-IL6 and GFAP-IFN mice, complement gene expression was widely dysregulated relative to wildtype controls. Chronic administration of a C5aR1 inhibitor did not significantly alter the behavioural, histopathological, or transcriptional profile of either murine model. Our results suggest that targeting C5aR1 does not observably impact the disease progression in these murine models of neuroinflammation. Collectively, these data offer insight into the relationship between IL-6 and IFN-a with C5aR1 and provide future avenues to explore how these cytokines may interact with other CS components in the murine brain.