Corrigendum: Immunoproteasome inhibition attenuates experimental psoriasis.

[This corrects the article DOI: 10.3389/fimmu.2022.1075615.].

Valosin-containing protein (VCP/p97) inhibition reduces viral clearance and induces toxicity associated with muscular damage.

Valosin-containing protein (VCP)/p97 has emerged as a central regulator of the ubiquitin-proteasome system by connecting ubiquitylation and degradation. The development of CB-5083, an ATPase D2-domain-selective and orally bioavailable inhibitor of VCP/p97, allows targeting of the ubiquitin-proteasome system in human diseases. In this study, we evaluated the effect of CB-5083 on the immune response in mice by using the lymphocytic choriomeningitis virus (LCMV) as an infection model. We demonstrate that LCMV infection increased the susceptibility to CB-5083 treatment in a CD8-independent manner. Administration of CB-5083 to mice reduced the cytotoxic T cell response and impaired viral clearance. Compared to uninfected cells, CB-5083 treatment enhanced the unfolded protein response in LCMV-infected cells. Administration of CB-5083 during the expansion of CD8+ T cells led to strong toxicity in mice within hours, which resulted in enhanced IL-6 levels in the serum and accumulation of poly-ubiquitinated proteins. Furthermore, we linked the observed toxicity to the specific formation of aggregates in the skeletal muscle tissue and the upregulation of both lactate dehydrogenase and creatine kinase in the serum.

Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome.

Polymyositis (PM) is a chronic autoimmune inflammatory myopathy resulting in muscle weakness. The limited approved therapies and their poor efficacy contribute to its comorbidity. We investigated the therapeutic use of ONX 0914 and KZR-616, selective inhibitors of the immunoproteasome, in C protein-induced myositis (CIM), a mouse model of PM that closely resembles the human disease. Diseased mice (day 13 postimmunization) were treated with 10 mg/kg ONX 0914, KZR-616, or vehicle on alternate days until day 28. Endpoints included muscle strength assessed by a grip strength meter, serum creatine kinase activity, histology, and immunohistochemistry analysis. Treatment with ONX 0914 or KZR-616 prevented the loss of grip strength in mice after CIM induction, while vehicle-treated animals displayed progressive muscle weakness. Immunoproteasome inhibition lowered PM-associated leukocyte infiltration of the muscle and prevented increased serum creatine kinase levels. LMP7-deficient mice were resistant to CIM induction, as they showed no alterations in grip strength or creatine kinase (CK) levels or muscular alterations. In conclusion, selective inhibition of the immunoproteasome displays therapeutic efficacy in a preclinical mouse model of PM with suppression of muscle inflammation and preservation of muscle strength. Positive results from this study support the rationale for using KZR-616 in clinical studies.

Immunoproteasome inhibition attenuates experimental psoriasis.

Introduction: Psoriasis is an autoimmune skin disease associated with multiple comorbidities. The immunoproteasome is a special form of the proteasome expressed in cells of hematopoietic origin. Methods: The therapeutic use of ONX 0914, a selective inhibitor of the immunoproteasome, was investigated in Card14ΔE138+/- mice, which spontaneously develop psoriasis-like symptoms, and in the imiquimod murine model. Results: In both models, treatment with ONX 0914 significantly reduced skin thickness, inflammation scores, and pathological lesions in the analyzed skin tissue. Furthermore, immunoproteasome inhibition normalized the expression of several pro-inflammatory genes in the ear and significantly reduced the inflammatory infiltrate, accompanied by a significant alteration in the αß+ and γδ+ T cell subsets. Discussion: ONX 0914 ameliorated psoriasis-like symptoms in two different murine psoriasis models, which supports the use of immunoproteasome inhibitors as a therapeutic treatment in psoriasis.