Immunoproteasome inhibition induces plasma cell apoptosis and preserves kidney allografts by activating the unfolded protein response and suppressing plasma cell survival factors

Li, Jun; Koerner, Julia; Basler, Michael; Brunner, Thomas; Kirk, Christopher J.; Groettrup, Marcus

doi:10.1016/j.kint.2018.10.022

Cited by 30 publications

(26 citation statements)

References 42 publications

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“…Moreover, we demonstrated intact effector T and B cell responses, as well as unaffected memory responses, in both ONX 0914-treated and LMP7-deficient C57BL/6 mice after CVB3 infection [3,38]. Altogether, we conclude that alterations of the adaptive immune response, which might be mediated by ONX 0914 [30,54], are not among its main effectors, leading to exacerbated pathology in CVB3-infected NMRI mice. Quite in contrast to its pleiotropic cellular functions in the regulation of inflammatory signaling cascades and in antigen presentation in the host cell, the UPS can also be utilized to control the abundance of viral proteins in infected cells [25].…”

Section: Discussionmentioning

confidence: 68%

“…These involve control of DAMP-or PAMP-triggered signaling responses, resulting in elevated production of cytokines, e.g., by innate myeloid cells, altered T cell activation and differentiation, B cell function, or immune cell survival [23][24][25]. Based on these multidimensional immune cellular functions, it was expected that i-proteasome inhibitors would be capable of hindering inflammation-driven carcinogenesis [26,27], autoimmune-related inflammation [20,28,29], or transplant rejection [22,30].…”

Section: Introductionmentioning

confidence: 99%

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ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage

Neumaier

Harel

Klingel

et al. 2020

Cells

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Inhibition of proteasome function by small molecules is highly efficacious in cancer treatment. Other than non-selective proteasome inhibitors, immunoproteasome-specific inhibitors allow for specific targeting of the proteasome in immune cells and the profound anti-inflammatory potential of such compounds revealed implications for inflammatory scenarios. For pathogen-triggered inflammation, however, the efficacy of immunoproteasome inhibitors is controversial. In this study, we investigated how ONX 0914, an immunoproteasome-selective inhibitor, influences CoxsackievirusB3 infection in NMRI mice, resulting in the development of acute and chronic myocarditis, which is accompanied by formation of the immunoproteasome in heart tissue. In groups in which ONX 0914 treatment was initiated once viral cytotoxicity had emerged in the heart, ONX 0914 had no anti-inflammatory effect in the acute or chronic stages. ONX 0914 treatment initiated prior to infection, however, increased viral cytotoxicity in cardiomyocytes, promoting infiltration of myeloid immune cells into the heart. At this stage, ONX 0914 completely inhibited the β5 subunit of the standard cardiac proteasome and less efficiently blocked its immunoproteasome counterpart LMP7. In conclusion, ONX 0914 unselectively perturbs cardiac proteasome function in viral myocarditis of NMRI mice, reduces the capacity of the host to control the viral burden and promotes cardiac inflammation.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage

Neumaier

Harel

Klingel

et al. 2020

Cells

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“…Targeting plasma cells in animal models for systemic lupus erythematosus and kidney transplantation has also been successful with the IP inhibitor ONX 0914 (23,62). In a kidney allotransplantation model in rats, we have shown that IP inhibition with ONX 0914 led to ubiquitinconjugate accumulation, the activation of the UPR, and the induction of apoptosis in plasma cells (63).…”

Section: Discussionmentioning

confidence: 89%

Immunoproteasome Inhibition Selectively Kills Human CD14+ Monocytes and as a Result Dampens IL-23 Secretion

Basler

Claus

Klawitter

et al. 2019

The Journal of Immunology

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MECL-1 (b2i), LMP2 (b1i), and LMP7 (b5i) are the proteolytically active subunits of the immunoproteasome (IP), a special type of proteasome mainly expressed in hematopoietic cells. Targeting the IP in autoimmune diseases proved to be therapeutically effective in preclinical mouse models. In endotoxin-stimulated human PBMCs, IP inhibition reduces the secretion of several proinflammatory cytokines, with the suppression of IL-23 being the most prominent. In this study, we investigated why the production of IL-23, a key mediator of inflammation in autoimmunity, is blocked when the IP is inhibited in LPS-stimulated human PBMCs. CD14 + monocytes could be identified as the main producers of IL-23 in LPS-stimulated PBMCs. We found that IP inhibition with the irreversible LMP7/LMP2 inhibitor ONX 0914 induced apoptosis in CD14 + monocytes, whereas CD4 + , CD3 + , CD19 + , and CD56 + cells remained unaffected. A high expression of IPs renders monocytes susceptible to IP inhibition, leading to an accumulation of polyubiquitylated proteins and the induction of the unfolded protein response. Similar to IP inhibition, inducers of the unfolded protein response selectively kill CD14 + monocytes in human PBMCs. The blockage of the translation in CD14 + monocytes protects these cells from ONX 0914-induced cell death, indicating that the IP is required to maintain protein turnover in monocytes. Taken together, our data reveal why IP inhibition is particularly effective in the suppression of IL-23-driven autoimmunity.

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“…Intriguingly, at least two key cytokines contributing to the plasma cell niche, TNF and IL-6, have been demonstrated to be dependent upon the immunoproteasome subunit LMP7 [48]. In agreement with this notion, Li, et al [49] reported that immunoproteasome inhibitor ONX 0914 can induce plasma cell apoptosis through activating the UPR and suppressing plasma cell survival factors in the bone marrow.…”

Section: B Cell Immunitymentioning

confidence: 82%

“…Thus, more evidence is needed to verify the conclusion of this trial and the efficacy of (immuno) proteasome inhibition in IgAN. As an autoimmune disease elicited by Gd-IgA1 antibodies, immunoproteasome inhibitors may be considered as a promising strategy due to its important role in plasma cells survival [49]. However, before the immunoproteasome becomes a therapeutic target in IgAN, further research is necessary to clarify whether and how the immunoproteasome participate in pathogenesis and/or progression of the disease.…”

Section: The Immunoproteasome As a Therapeutic Targetmentioning

confidence: 99%

Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives

Gan

Zhou³

et al. 2020

Int. J. Biol. Sci.

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IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and renal failure. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the immunoproteasome probably plays an important role in IgAN. The immunoproteasome is a proteasome variant that is expressed when cells are stressed or receive inflammatory signals. While immunoproteasome is suggested to be mainly involved in major histocompatibility complex-I (MHC-I) antigen presentation, recent studies indicate that it may assert broad functions in trafficking events that activate both innate and adaptive immunity. In this review, we first summarize new insights into its functions in immunity, and discuss how it underlies its associations with IgAN. We also highlight its potential as a therapeutic target for the future.

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Immunoproteasome inhibition induces plasma cell apoptosis and preserves kidney allografts by activating the unfolded protein response and suppressing plasma cell survival factors

Cited by 30 publications

References 42 publications

ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage

ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage

Immunoproteasome Inhibition Selectively Kills Human CD14+ Monocytes and as a Result Dampens IL-23 Secretion

Immunoproteasome in IgA Nephropathy: State-of-Art and Future Perspectives

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