Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome

Basler, Michael; Dajee, Maya; Moll, Carlo; Groettrup, Marcus; Kirk, Christopher J.

doi:10.4049/jimmunol.0903182

Cited by 221 publications

(268 citation statements)

References 47 publications

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“…In addition to RA, similar anti-inflammatory activity of ONX 0914 was observed in a mouse model of colitis. 57 In todate published works and in our experiments, we did not observe tumor formation or delay in muscle differentiation indicating that the ONX-0914 dosage used did not provide such possible side effects. Therefore, further studies are needed that focus on ONX-0914 treatment to translate in DMD patients the suppression of the i-proteasome as new promising therapeutic option.…”

Section: Discussionsupporting

confidence: 59%

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

et al. 2016

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Duchenne muscular dystrophy is an inherited fatal genetic disease characterized by mutations in dystrophin gene, causing membrane fragility leading to myofiber necrosis and inflammatory cell recruitment in dystrophic muscles. The resulting environment enriched in proinflammatory cytokines, like IFN-γ and TNF-α, determines the transformation of myofiber constitutive proteasome into the immunoproteasome, a multisubunit complex involved in the activation of cell-mediate immunity. This event has a fundamental role in producing peptides for antigen presentation by MHC class I, for the immune response and also for cytokine production and T-cell differentiation. Here, we characterized for the first time the presence of T-lymphocytes activated against revertant dystrophin epitopes, in the animal model of Duchenne muscular dystrophy, the mdx mice. Moreover, we specifically blocked i-proteasome subunit LMP7, which was up-regulated in dystrophic skeletal muscles, and we demonstrated the rescue of the dystrophin expression and the amelioration of the dystrophic phenotype. The i-proteasome blocking lowered myofiber MHC class I expression and self-antigen presentation to T cells, thus reducing the specific antidystrophin T cell response, the muscular cell infiltrate, and proinflammatory cytokine production, together with muscle force recovery. We suggest that i-proteasome inhibition should be considered as new promising therapeutic approach for Duchenne muscular dystrophy pathology.

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Section: Discussionsupporting

confidence: 59%

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

et al. 2016

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“…additional immunological functions. Immunoproteasome deficiency or inhibition affects T cell survival, expansion, and differentiation (Basler et al, 2004;Chen et al, 2001;Kalim et al, 2012;Moebius et al, 2010;Muchamuel et al, 2009;Zaiss et al, 2008), cytokine production (Basler et al, 2011;Basler et al, 2010;Basler et al, 2014;Muchamuel et al, 2009), and progression of autoimmune conditions (Basler et al, 2015). Moreover, mutations in LMP7 and LMP2 in humans cause complex autoimmune and inflammatory phenotypes .…”

Section: Discussionmentioning

confidence: 99%

Immunoproteasome subunit deficiency has no influence on the canonical pathway of NF-κB activation

Bitzer

Basler

Krappmann

et al. 2017

Molecular Immunology

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a b s t r a c tActivation of the pro-inflammatory transcription factor NF-B requires signal-induced proteasomal degradation of the inhibitor of NF-B (IB) in order to allow nuclear translocation. Most cell types are capable of expressing two types of 20S proteasome core particles, the constitutive proteasome and immunoproteasome. Inducible under inflammatory conditions, the immunoproteasome is mainly characterized through an altered cleavage specificity compared to the constitutive proteasome. However, the question whether immunoproteasome subunits affect NF-B signal transduction differently from constitutive subunits is still up for debate. To study the effect of immunoproteasomes on LPS-or TNF-␣-induced NF-B activation, we used IFN-␥ stimulated peritoneal macrophages and mouse embryonic fibroblasts derived from mice deficient for the immunoproteasome subunits low molecular mass polypeptide (LMP) 2, or LMP7 and multicatalytic endopeptidase complex-like 1 (MECL-1). Along the canonical signaling pathway of NF-B activation no differences in the extent and kinetic of IB degradation were observed. Neither the nuclear translocation and DNA binding of NF-B nor the production of the NF-B dependent cytokines TNF-␣, IL-6, and IL-10 differed between immunoproteasome deficient and proficient cells. Hence, we conclude that immunoproteasome subunits have no specialized function for canonical NF-B activation.

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“…and has shown efficacy in mouse models of inflammatory bowel disease, arthritis, systemic lupus erythematosus, multiple sclerosis, and type I diabetes in association with modulation of the function of Th1 and Th17 cells (10)(11)(12)(13). However, to our knowledge, selective immunoproteasome inhibitors have not been tested for their role in promoting allograft acceptance, nor have effects been described on T-cell exhaustion and coinhibitory markers on DCs.…”

Section: Significancementioning

confidence: 99%

Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice

Karreci

Fan

Uehara

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Constitutive proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. An isoform of proteasome, the immunoproteasome (i-20S), is highly expressed in human T cells, dendritic cells (DCs), and B cells, suggesting that it could be a potential target for inflammatory diseases, including those involving autoimmunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit β5i that has thousands-fold selectivity over constitutive β5c. DPLG3 suppressed cytokine release from blood mononuclear cells and the activation of DCs and T cells, diminished accumulation of effector T cells, promoted expression of exhaustion and coinhibitory markers on T cells, and synergized with CTLA4-Ig to promote long-term acceptance of cardiac allografts across a major histocompatibility barrier. These findings demonstrate the potential value of using brief posttransplant immunoproteasome inhibition to entrain a long-term response favorable to allograft survival as part of an immunomodulatory regimen that is neither broadly immunosuppressive nor toxic.

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Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome

Abstract: Material

Cited by 221 publications

References 47 publications

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

Immunoproteasome subunit deficiency has no influence on the canonical pathway of NF-κB activation

Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice

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