Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody‐secreting cells

Abstract

Objective We postulated that proteasome inhibition (PI) may be useful in the treatment of SLE by targeting plasmacytoid dendritic cells (pDCs) and plasma cells (PCs), both critical to disease pathogenesis. Methods Lupus prone mice were treated with the non-selective PIs carfilzomib and bortezomib, the LMP7-selective immunoproteasome inhibitor ONX 0914, or vehicle control. Tissues were harvested and analyzed by flow cytometry using standard markers. Nephritis was monitored by proteinuria and kidney harvest. Serum anti-dsDNA levels were measured by ELISA and total IgG and dsDNA antibody secreting cells (ASC) by ELIspot. Human PBMCs or mouse bone marrow cells were incubated with TLR agonists and PIs and interferon α measured by ELISA and flow cytometry. Results Early treatment of lupus prone mice with the dual targeting PIs carfilzomib or bortezomib or the immunoproteasome specific inhibitor ONX 0914 prevented disease progression, and treatment of mice with established disease dramatically abrogated nephritis. Treatment had profound effects on plasma cells with greater reductions in autoreactive than total IgG ASCs, an effect that became more pronounced with prolonged treatment, and was reflected in decreasing serum autoantibodies. Remarkably, proteasome inhibition efficiently suppressed production of interferon α by toll-like receptor activated pDCs in vitro and in vivo, an effect mediated by both an inhibition of pDC survival and function. Conclusions Inhibition of the immunoproteasome is equally efficacious to dual targeting agents in preventing lupus disease progression by targeting two critical pathways in disease pathogenesis, type I interferon activation and autoantibody production by plasma cells.

No evidence for immunoproteasomes in chicken lymphoid organs and activated lymphocytes

“…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).…”

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

“…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.…”

The Pathogenesis of Lupus Nephritis

“…97 Massive antibody production in plasma cells involves the intracellular proteasome complex for protein processing. The proteasome inhibitor bortezomib was proven to be effective in mouse models of LN, 98,99 but clinical trials with bortezomib in human LN is still pending.…”