title: Inhibition and deficiency of the immunoproteasome subunit LMP7 attenuates LCMV-induced meningitis.
abstract: In addition to antigen processing, immunoproteasomes were recently shown to exert 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 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 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.
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.|Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Konstanz, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mundt
authors.affiliation: Theodor Kocher Institute, University of Bern, Bern, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.affiliation: Onyx Pharmaceuticals, South San Francisco, CA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kirk
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.|Biotechnology Institute Thurgau at the University of Konstanz (BITg), Kreuzlingen, Switzerland.
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.|Biotechnology Institute Thurgau at the University of Konstanz (BITg), Kreuzlingen, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Basler
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001117:Arenaviridae Infections / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex
keywords: CNS inflammation; Cytotoxic T cells; Immunoproteasome; LMP7; Lymphocytic choriomeningitis virus