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在系统性红斑狼疮模型中，组胺类似物氯苯丙哌嗪通过靶向CXCR4来调节IRF7磷酸化和干扰素生成。

The histamine analogue clobenpropit modulates IRF7 phosphorylation and interferon production by targeting CXCR4 in systemic lupus erythematosus models.

作者信息

Bekaddour Nassima, Smith Nikaïa, Caspar Birgit, Grinberg Severine, Giorgiutti Stephane, Rodeschini Vincent, Dupuy Stephanie, Leboulanger Nicolas, Duffy Darragh, Soulas-Sprauel Pauline, Gies Vincent, Korganow Anne-Sophie, Nisole Sébastien, Herbeuval Jean-Philippe

机构信息

Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR), Université Paris Cité, Paris, France.

Team Chemistry & Biology, Modeling & Immunology for Therapy (CBMIT), Paris, France.

出版信息

Front Immunol. 2024 Dec 16;15:1490593. doi: 10.3389/fimmu.2024.1490593. eCollection 2024.

DOI:10.3389/fimmu.2024.1490593
PMID:
39737176
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11682962/
Abstract

INTRODUCTION

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by an overactive immune response, particularly involving excessive production of type I interferons. This overproduction is driven by the phosphorylation of IRF7, a crucial factor in interferon gene activation. Current treatments for SLE are often not very effective and can have serious side effects.

METHODS

Our study introduces clobenpropit, a histamine analogue, as a potential new therapy targeting the CXCR4 receptor to reduce IRF7 phosphorylation and subsequent interferon production. We employed various laboratory techniques to investigate how clobenpropit interacts with CXCR4 and its effects on immune cells from healthy individuals and SLE patients.

RESULTS

Clobenpropit binds effectively to CXCR4, significantly inhibiting IRF7 phosphorylation and reducing interferon production. Additionally, clobenpropit lowered levels of pro-inflammatory cytokines in a mouse model of lupus, demonstrating efficacy comparable to the standard treatment, prednisolone.

DISCUSSION

These results suggest that clobenpropit could be a promising new treatment for SLE, offering a targeted approach with potential advantages over current therapies.

摘要

引言

系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是免疫反应过度活跃，特别是涉及I型干扰素的过度产生。这种过度产生是由IRF7的磷酸化驱动的，IRF7是干扰素基因激活中的关键因素。目前用于治疗SLE的方法通常效果不佳，并且可能有严重的副作用。

方法

我们的研究引入了一种组胺类似物氯苯丙哌嗪，作为一种潜在的新疗法，靶向CXCR4受体以减少IRF7磷酸化及随后的干扰素产生。我们采用了各种实验室技术来研究氯苯丙哌嗪如何与CXCR4相互作用及其对健康个体和SLE患者免疫细胞的影响。

结果

氯苯丙哌嗪能有效结合CXCR4，显著抑制IRF7磷酸化并减少干扰素产生。此外，在狼疮小鼠模型中，氯苯丙哌嗪降低了促炎细胞因子水平，显示出与标准治疗药物泼尼松龙相当的疗效。

讨论

这些结果表明，氯苯丙哌嗪可能是一种有前景的SLE新疗法，提供了一种靶向治疗方法，相对于目前的疗法具有潜在优势。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/3da44ebcea0e/fimmu-15-1490593-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/532462f40d82/fimmu-15-1490593-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/2deaa62c745a/fimmu-15-1490593-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/fff41ba5024c/fimmu-15-1490593-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/919c43727b89/fimmu-15-1490593-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/05cc4a4fb6b4/fimmu-15-1490593-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/3da44ebcea0e/fimmu-15-1490593-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/532462f40d82/fimmu-15-1490593-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/2deaa62c745a/fimmu-15-1490593-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/fff41ba5024c/fimmu-15-1490593-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/919c43727b89/fimmu-15-1490593-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/05cc4a4fb6b4/fimmu-15-1490593-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbc8/11682962/3da44ebcea0e/fimmu-15-1490593-g006.jpg

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