A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis

Abstract

The immunoproteasome, a distinct class of proteasome found predominantly in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on class I major histocompatibility complexes (MHC-I). However, a specific role for the immunoproteasome in regulating other facets of immune responses has not been established. We describe here the characterization of PR-957, a selective inhibitor of low-molecular mass polypeptide-7 (LMP7, encoded by Psmb8), the chymotrypsin-like subunit of the immunoproteasome. PR-957 blocked presentation of LMP7-specific, MHC-I-restricted antigens in vitro and in vivo. Selective inhibition of LMP7 by PR-957 blocked production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and resulted in reductions in cellular infiltration, cytokine production and autoantibody levels. These studies reveal a unique role for LMP7 in controlling pathogenic immune responses and provide a therapeutic rationale for targeting LMP7 in autoimmune disorders.

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

“…The HY-Ag-derived MHC-I epitope UTY 246-254 is LMP7 and LMP2 dependent Generation of the CTL epitope UTY 246-254 (ubiquitously transcribed tetratricopeptide repeat gene, Y-linked), derived from the endogenously expressed Y-chromosome-encoded HY-Ag, has been demonstrated to be LMP7 dependent (14,33). To confirm this result and to investigate whether the other immunoproteasome subunits LMP2 and MECL-1 were similarly affecting this epitope, UTY 246-254 presentation on the H-2D b class I molecule of malederived splenocytes was determined with a UTY 246-254 -specific T cell hybridoma in lacZ assays (Fig.…”

“…The immunosubunits play a pivotal role in class I ligand generation, and therefore shape the naive CD8-T cell repertoire in the thymus and cytotoxic T cell responses in the periphery (9)(10)(11)(12)(13). Recently, novel functions of immunoproteasomes in autoimmune diseases, T cell expansion, and protection from immunopathological damage in the brain have been proposed (14)(15)(16)(17).…”

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

“…The immunoproteasome was shown to support the development of inflammatory T helper cells of the Th1 and Th17 type and to promote the production of pro-inflammatory cytokine responses Muchamuel et al 2009). The inhibitor ONX0914 (formerly named PR-957) irreversibly blocks the activity of the immunoproteasome subunit β5i in mice and humans.…”

“…The inhibitor ONX0914 (formerly named PR-957) irreversibly blocks the activity of the immunoproteasome subunit β5i in mice and humans. It suppresses the production of pro-inflammatory cytokines and the differentiation of Th1 and Th17 T helper cells while regulatory T cells are promoted and Th2 cells remain unaffected (Kalim et al 2012;Muchamuel et al 2009). In different mouse models, the treatment with ONX0914 suppressed autoimmune disease like rheumatoid arthritis, diabetes (Muchamuel et al 2009), colitis , systemic lupus erythematosus (Ichikawa et al 2012), and experimental autoimmune encephalomyelitis (Basler et al 2014).…”

“…It suppresses the production of pro-inflammatory cytokines and the differentiation of Th1 and Th17 T helper cells while regulatory T cells are promoted and Th2 cells remain unaffected (Kalim et al 2012;Muchamuel et al 2009). In different mouse models, the treatment with ONX0914 suppressed autoimmune disease like rheumatoid arthritis, diabetes (Muchamuel et al 2009), colitis , systemic lupus erythematosus (Ichikawa et al 2012), and experimental autoimmune encephalomyelitis (Basler et al 2014). Additionally, this is affirmed by reports that in humans, mutations in the gene encoding for β5i are associated with autoinflammatory disease (Agarwal et al 2010;Arima et al 2011;Kitamura et al 2011).…”