Dataset Information

Immunoproteasome inhibition attenuates experimental psoriasis.

ABSTRACT:

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 αβ⁺ 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.

SUBMITTER: Del Rio Oliva M

PROVIDER: S-EPMC9798438 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Immunoproteasome inhibition attenuates experimental psoriasis.

Del Rio Oliva Marta M Mellett Mark M Basler Michael M

Frontiers in immunology 20221214

<h4>Introduction</h4>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.<h4>Methods</h4>The therapeutic use of ONX 0914, a selective inhibitor of the immunoproteasome, was investigated in <i>Card14ΔE138<sup>+/-</sup></i> mice, which spontaneously develop psoriasis-like symptoms, and in the imiquimod murine model.<h4>Results</h4>In both models, treatment with ONX 0914 s ...[more]

PMID: 36591277

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Project description:BackgroundAbdominal aortic aneurysms (AAA) are characterized by vascular inflammation and remodeling that can lead to aortic rupture resulting in significant mortality. Pannexin-1 channels on endothelial cells (ECs) can modulate ATP secretion to regulate the pathogenesis of AAA formation. Our hypothesis focused on potential of spironolactone to inhibit EC-mediated ATP release for the mitigation of AAA formation.MethodsA topical elastase AAA model was used initially in C57BL/6 (wild-type; WT) male mice. Mice were administered either a vehicle control (saline) or spironolactone and analyzed on day 14. In a second chronic AAA model, mice were subjected to elastase and β-aminopropionitrile (BAPN) treatment with/without administration of spironolactone to pre-formed aneurysms starting on day 14 and analyzed on day 28. Aortic diameter was evaluated by video micrometry and aortic tissue was analyzed for cytokine expression and histology. ATP measurement and matrix metalloproteinase (MMP2) activity was evaluated in aortic tissue on days 14 or -28. In vitro studies were performed to evaluate the crosstalk between aortic ECs with macrophages or smooth muscle cells.ResultsIn the elastase AAA model, spironolactone treatment displayed a significant decrease in aortic diameter compared to elastase-treated controls on day 14. A significant increase in smooth muscle α-actin expression as well as decrease in elastic fiber disruption and immune cell (macrophages and neutrophils) infiltration was observed in mice treated with spironolactone compared to saline-treated controls. Spironolactone treatment also significantly mitigated pro-inflammatory cytokine expression, MMP2 activity and ATP content in aortic tissue compared to controls. Moreover, in the chronic AAA model, spironolactone treatment of pre-formed aneurysms significantly attenuated vascular inflammation and remodeling to attenuate the progression of AAAs compared to controls. Mechanistically, in vitro data demonstrated that spironolactone treatment attenuates extracellular ATP release from endothelial cells to mitigate macrophage activation (IL-1β and HMGB1 expression) and smooth muscle cell-dependent vascular remodeling (MMP2 activity).ConclusionThese results demonstrate that spironolactone can mitigate aortic inflammation and remodeling to attenuate AAA formation as well as decrease growth of pre-formed aneurysms via inhibition of EC-dependent ATP release. Therefore, this study implicates a therapeutic application of spironolactone in the treatment of AAAs.

Dataset Information

Immunoproteasome inhibition attenuates experimental psoriasis.

Introduction

Methods

Results

Discussion

Publications

Immunoproteasome inhibition attenuates experimental psoriasis.

Similar Datasets

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