Inhibition and deficiency of the immunoproteasome subunit LMP7 attenuates LCMV-induced meningitis

Abstract

In addition to antigen processing, immunoproteasomes were recently shown to exert additional functions influencing cytokine production by monocytes and T cells, T helper cell differentiation, and T-cell survival. Moreover, selective inhibition of the immunoproteasome subunit LMP7 ameliorated symptoms of autoimmune diseases including CD4(+) T cell mediated experimental autoimmune encephalomyelitis (EAE). In this study, we show that LMP7 also plays a crucial role in the pathogenesis of lymphocytic choriomeningitis virus (LCMV)-induced meningitis mediated by cytotoxic T cells (CTLs). Mice lacking functional LMP7 display delayed and reduced clinical signs of disease accompanied by a strongly decreased inflammatory infiltration into the brain. Interestingly, we found that selective inhibition and genetic deficiency of LMP7 affect the pathogenesis of LCMV-induced meningitis in a distinct manner. Our findings support the important role of LMP7 in inflammatory disorders and suggest immunoproteasome inhibition as a novel strategy against inflammation-induced neuropathology in the CNS. This article is protected by copyright. All rights reserved.