Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis

作者：Conor Mc Guire, Lynn Elton, Peter Wieghofer, Jens Staal, Sofie Voet, Annelies Demeyer, Daniel Nagel, Daniel Krappmann, Marco Prinz, Rudi Beyaert, Geert Loo · 发表于：Journal of Neuroinflammation · 年份：2014 · DOI：10.1186/1742-2094-11-124 · 被引用次数：82 · 研究领域：NF-κB Signaling Pathways、Cell death mechanisms and regulation、Protein Kinase Regulation and GTPase Signaling

BACKGROUND: The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for lymphocyte activation through signaling to the transcription factor NF-κB. Besides functioning as a scaffold signaling protein, MALT1 also acts as a cysteine protease that specifically cleaves a number of substrates and contributes to specific T cell receptor-induced gene expression. Recently, small molecule inhibitors of MALT1 proteolytic activity were identified and shown to have promising anticancer properties in subtypes of B cell lymphoma. However, information on the therapeutic potential of small compound inhibitors that target MALT1 protease activity in autoimmunity is still lacking. METHODS: The present study aimed to elucidate whether MALT1 protease inhibitors are also useful in the treatment of lymphocyte-mediated autoimmune pathologies such as multiple sclerosis (MS). For this, we studied the therapeutic potential of a recently identified inhibitor of MALT1 protease activity, the phenothiazine derivative mepazine, in the context of experimental autoimmune encephalomyelitis (EAE), the main animal model for MS. RESULTS: We demonstrate that administration of mepazine prophylactically or after disease onset, can attenuate EAE. Importantly, while complete absence of MALT1 affects the differentiation of regulatory T (Treg) cells in vivo, the MALT1 protease inhibitor mepazine did not affect Treg development. CONCLUSIONS: Altogether, these data indicate tha...