Caspase-1 regulates the inflammatory process leading to autoimmune demyelination.
T cell-mediated inflammation is considered to play a key role in the pathogenic mechanisms sustaining multiple sclerosis (MS). Caspase-1, formerly designated IL-1beta-converting enzyme, is crucially involved in immune-mediated inflammation because of its pivotal role in regulating the cellular export of IL-1beta and IL-18. We studied the role of caspase-1 in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. Caspase-1 is transcriptionally induced during EAE, and its levels correlate with the clinical course and transcription rate of proinflammatory cytokines such as TNF-alpha, IL-1beta, IFN-gamma, and IL-6. A reduction of EAE incidence and severity is observed in caspase-1-deficient mice, depending on the immunogenicity and on the amount of the encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide used. In caspase-1-deficient mice, reduced EAE incidence correlates with defective development of anti-MOG IFN-gamma-producing Th1 cells. Finally, pharmacological blockade of caspase-1 in Biozzi AB/H mice, immunized with spinal cord homogenate or MOG35-55 peptide, by the caspase-1-inhibitor Z-Val-Ala-dl -Asp-fluoromethylketone, significantly reduces EAE incidence in a preventive but not in a therapeutic protocol. These results indicate that caspase-1 plays an important role in the early stage of the immune-mediated inflammatory process leading to EAE, thus representing a possible therapeutic target in the acute phase of relapsing remitting MS.
Furlan
R
R
Experimental Neuroimmunotherapy Unit, Department of Biotechnology, San Raffaele Scientific Institute, Milan, Italy.
Martino
G
G
Galbiati
F
F
Poliani
P L
PL
Smiroldo
S
S
Bergami
A
A
Desina
G
G
Comi
G
G
Flavell
R
R
Su
M S
MS
Adorini
L
L
D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage; D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage; D004198:Disease Susceptibility; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D015918:Infusion Pumps, Implantable; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020170:Caspase 1