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

Journal of Neuroinflammation

Geert van Loo²  Rudi Beyaert²  Marco Prinz¹  Daniel Krappmann³  Daniel Nagel³  Annelies Demeyer²  Sofie Voet²  Jens Staal²  Peter Wieghofer¹  Lynn Elton²  Conor Mc Guire² 

[1] BIOSS Centre for Biological Signaling Studies, University of Freiburg, Breisacherstrasse 64, D79106 Freiburg, Germany;Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium;Institute for Molecular Toxicology and Pharmacology, Cellular Signal Integration, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany

关键词: demyelination;    mepazine;    MALT1;    experimental autoimmune encephalomyelitis;    multiple sclerosis;   

Others  :  1151340
DOI  :  10.1186/1742-2094-11-124

 received in 2014-01-23, accepted in 2014-07-08,  发布年份 2014

【 摘 要 】

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 that small molecule inhibitors of MALT1 not only hold great promise for the treatment of B cell lymphomas but also for autoimmune disorders such as MS.

【 授权许可】

   
2014 Mc Guire et al.; licensee BioMed Central Ltd.

【 图 表 】

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