Caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate dendric cell IL-1-IL-17 pathway.

ABSTRACT

BACKGROUND: IL-1ß has been shown to play a pivotal role in autoimmunity. Cysteinyl aspartate-specific proteinase-1 (caspase-1) inhibitor may be an important drug target for autoimmune diseases. However, the effects of caspase-1 inhibitor on myasthenia gravis (MG) remain undefined. METHODS: To investigate the effects of caspase-1 inhibitor on experimental autoimmune myasthenia gravis (EAMG), an animal model of MG, caspase-1 inhibitor was administered to Lewis rats immunized with region 97-116 of the rat AChR α subunit (R97-116 peptide) in complete Freund's adjuvant. The immunophenotypical characterization by flow cytometry and the levels of autoantibody by ELISA were carried out to evaluate the neuroprotective effect of caspase-1 inhibitor. RESULTS: We found that caspase-1 inhibitor improved EAMG clinical symptom, which was associated with decreased IL-17 production by CD4+ T cells and γδ T cells, lower affinity of anti-R97-116 peptide IgG. Caspase-1 inhibitor decreased expression of CD80, CD86, and MHC class II on DCs, as well as intracellular IL-1ß production from DCs. In addition, caspase-1 inhibitor treatment inhibited R97-116 peptide-specific cell proliferation and decreased follicular helper T cells relating to EAMG development. CONCLUSIONS: Our results suggest that caspase-1 inhibitor ameliorates experimental autoimmune myasthenia gravis by innate DC IL-1-IL-17 pathway and provides new evidence that caspase-1 is an important drug target in the treatment of MG and other autoimmune diseases.