Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation.
Multiple sclerosis (MS) is a detrimental disease of the central nervous system (CNS) leading to long-term disability. In the course of animal models of multiple sclerosis (experimental autoimmune encephalomyelitis), we find enhanced activity of proteasome subunits beta1i, beta2, beta2i and beta5 in the CNS. We demonstrate that pharmacological inhibition of the proteasome by bortezomib ameliorates experimental autoimmune encephalomyelitis in mice and rats in prophylactic and therapeutic treatment with reduced numbers of T-cells secreting proinflammatory cytokines. The anti-inflammatory effect of proteasome inhibition was accompanied by reduced NF-kappaB activity in the CNS and lymphoid organs. The combined inhibition of proteasomes and lysosomal proteases involved in major histocompatibility complex II antigen presentation further improved therapeutic efficacy. We suggest proteasome inhibition alone or in combination with inhibition of lysosomal proteases as a novel therapeutic strategy against inflammation-induced neurodegeneration in the CNS. We demonstrate the impact of the proteasome and lysosomal proteases on development of autoimmunity.
Fissolo
Nicolas
N
Experimental Neuroimmunology, Department of General Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Kraus
Marianne
M
Reich
Michael
M
Ayturan
Miriam
M
Overkleeft
Herman
H
Driessen
Christoph
C
Weissert
Robert
R
D000818:Animals; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D001921:Brain / Q000378:metabolism; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004151:Dipeptides / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D008221:Lymphoid Tissue / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B / Q000378:metabolism; D009457:Neuroglia / Q000201:enzymology; D009474:Neurons / Q000201:enzymology; D010446:Peptide Fragments / Q000276:immunology; D011480:Protease Inhibitors / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D051381:Rats; D013450:Sulfones / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology
D001897:Boronic Acids; D004151:Dipeptides; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; C532594:N-morpholinourea-leucine-homophenylalanine-phenyl-vinylsulfone; D016328:NF-kappa B; D010446:Peptide Fragments; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D013450:Sulfones; C445081:myelin oligodendrocyte glycoprotein (35-55); D000069286:Bortezomib; D002403:Cathepsins; C028217:cathepsin S; D046988:Proteasome Endopeptidase Complex