Caspase-1 regulates the inflammatory process leading to autoimmune demyelination

Roberto Furlan, Gianvito Martino, Francesca Galbiati, Pietro L. Poliani, Simona Smiroldo, Alessendra Bergami, Gaetano Desina, Giancarlo Comi, Richard Flavell, Michael S. Su, Luciano Adorini

Research output: Contribution to journalArticle

Abstract

T cell-mediated inflammation is considered to play a key role in the pathogenic mechanisms sustaining multiple sclerosis (MS). Caspase-1, formerly designated IL-1β-converting enzyme, is crucially involved in immune-mediated inflammation because of its pivotal role in regulating the cellular export of IL-1β 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-α, IL-1β, IFN-γ 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-γ-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.

Original languageEnglish
Pages (from-to)2403-2409
Number of pages7
JournalJournal of Immunology
Volume163
Issue number5
Publication statusPublished - Sep 1 1999

ASJC Scopus subject areas

  • Immunology

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    Furlan, R., Martino, G., Galbiati, F., Poliani, P. L., Smiroldo, S., Bergami, A., Desina, G., Comi, G., Flavell, R., Su, M. S., & Adorini, L. (1999). Caspase-1 regulates the inflammatory process leading to autoimmune demyelination. Journal of Immunology, 163(5), 2403-2409.