3 years ago

Amelioration of autoimmunity with an inhibitor selectively targeting all active centers of the immunoproteasome

Elmer Maurits, Gerjan Bruin, Herman S Overkleeft, Michael Basler, Marcus Groettrup, Julia Koerner
Background and Purpose MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome, a special type of proteasome mainly expressed in hematopoietic cells. Targeting LMP7 has been shown to be therapeutically effective in pre-clinical models of autoimmune diseases. In this study, a recently described inhibitor of the immunoproteasome LU-005i was investigated with respect to selectivity and biological activity. Experimental Approach The specificity of LU-005i and other immunoproteasome selective inhibitors was characterized using fluorogenic peptide substrates. The effect of proteasome inhibition on cytokine release was investigated with endotoxin-stimulated mouse splenocytes or human PBMCs. Measurement of weight loss and colon length was used to analyse the effect of proteasome inhibition on inflammatory bowel disease in the dextran sulfate sodium (DSS)-induced colitis model. Key Results LU-005i is the first human and mouse immunoproteasome selective inhibitor targeting all three proteolytically active immunoproteasome subunits. Cytokine secretion of LU-005i-exposed endotoxin-stimulated mouse splenocytes or human PBMCs was strongly reduced. Furthermore, differentiation of naïve T helper cells to T helper 17 cells was impaired in the presence of LU-005i. Additionally, LU-005i ameliorated DSS-induced colitis. Conclusion and Implications This study with a novel pan-immunoproteasome inhibitor substantiates that the immunoproteasome is a promising drug target for the treatment of inflammatory diseases and that exclusive inhibition of LMP7 is not necessary for therapeutic effectiveness. Our results will promote the design of new generations of immunoproteasome inhibitors with optimal therapeutic efficacy for clinical use in the treatment of autoimmunity and cancer.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14069

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