Systemic sterile induced-co-expression of IL-12 and IL-18 drive IFN-γ-dependent activation of microglia and recruitment of MHC-II-expressing inflammatory monocytes into the brain

The development of neuroinflammation, as well as the progression of several neurodegenerative diseases, has been associated with the activation and mobilization of the peripheral immune system due to systemic inflammation. However, the mechanism by which this occurs remains unclear. Here, we addressed the effect of systemic sterile induced-co-expression of IL-12 and IL-18, in the establishment of a novel cytokine-mediated model of neuroinflammation. Following peripheral hydrodynamic shear of IL-12 plus IL-18 cDNAs in C57BL/6 mice, we induced systemic and persistent level of IL-12, which in turn promoted the elevation of circulating pro inflammatory cytokines TNF-alpha and IFN-gamma, accompanied with splenomegaly. Moreover, even though we identified an increased gene expression of both TNF-alpha and IFN-gamma in the brain, we observed that only IFN-gamma, but not TNF-alpha signaling through its type I receptor, was required to induce both the trafficking of leukocytes from the periphery toward the brain and upregulate MHC-II in microglia and inflammatory monocytes. Therefore, only TNF-alpha was shown to be dispensable, revealing an IFN-gamma-dependent activation of microglia and recruitment of leukocytes, particularly of highly activated inflammatory monocytes. Taken together, our results argue for a systemic cytokine-mediated establishment and development of neuroinflammation, having identified IFN-gamma as a potential target for immunomodulation.

Automated summary

The development of neuroinflammation and progression of neurodegenerative diseases are associated with the activation and mobilization of the peripheral immune system due to systemic inflammation. This study investigated the effects of systemic sterile induced-co-expression of IL-12 and IL-18 on the establishment of a cytokine-mediated model of neuroinflammation.