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一种对CXCL12/SDF-1α具有选择性的中性配体，在MRL/Lpr狼疮易感小鼠中具有有益的调节功能。

A Selective Neutraligand for CXCL12/SDF-1α With Beneficial Regulatory Functions in MRL/Lpr Lupus Prone Mice.

作者信息

Schall Nicolas, Daubeuf François, Marsol Claire, Gizzi Patrick, Frossard Nelly, Bonnet Dominique, Galzi Jean-Luc, Muller Sylviane

机构信息

CNRS UMR7242, Biotechnology and Cell Signaling, Ecole Supérieure de Biotechnologie de Strasbourg, Strasbourg University/Strasbourg Drug Discovery and Development Institute (IMS), Strasbourg, France.

CNRS UMR7200, Laboratoire d'innovation Thérapeutique, Faculté de Pharmacie, Strasbourg University/Strasbourg Drug Discovery and Development Institute (IMS), Strasbourg, France.

出版信息

Front Pharmacol. 2021 Oct 21;12:752194. doi: 10.3389/fphar.2021.752194. eCollection 2021.

DOI:10.3389/fphar.2021.752194
PMID:34744730
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8566942/
Abstract

Dysregulation of CXCL12/SDF-1-CXCR4/CD184 signaling is associated with inflammatory diseases and notably with systemic lupus erythematosus. Issued from the lead molecule chalcone-4, the first neutraligand of the CXCL12 chemokine, LIT-927 was recently described as a potent analogue with improved solubility and stability. We aimed to investigate the capacity of LIT-927 to correct immune alterations in lupus-prone MRL/lpr mice and to explore the mechanism of action implemented by this small molecule in this model. We found that in contrast to AMD3100, an antagonist of CXCR4 and agonist of CXCR7, LIT-927 reduces the excessive number of several B/T lymphocyte subsets occurring in the blood of sick MRL/lpr mice (including CD3/CD4/CD8/B220 double negative T cells). , LIT-927 downregulated the overexpression of several activation markers on splenic MRL/lpr lymphocytes. It exerted effects on the CXCR4 pathway in MRL/lpr CD4 T spleen cells. The results underline the importance of the CXCL12/CXCR4 axis in lupus pathophysiology. They indicate that neutralizing CXCL12 by the neutraligand LIT-927 can attenuate hyperactive lymphocytes in lupus. This mode of intervention might represent a novel strategy to control a common pathophysiological mechanism occurring in inflammatory diseases.

摘要

CXCL12/SDF-1-CXCR4/CD184信号失调与炎症性疾病相关，尤其是与系统性红斑狼疮有关。LIT-927由先导分子查耳酮-4衍生而来，是CXCL12趋化因子的首个中性配体，最近被描述为一种具有改善溶解性和稳定性的强效类似物。我们旨在研究LIT-927纠正狼疮易感MRL/lpr小鼠免疫改变的能力，并探索该小分子在该模型中实施的作用机制。我们发现，与CXCR4拮抗剂和CXCR7激动剂AMD3100不同，LIT-927减少了患病MRL/lpr小鼠血液中出现的几种B/T淋巴细胞亚群的过量数量（包括CD3/CD4/CD8/B220双阴性T细胞）。此外，LIT-927下调了脾脏MRL/lpr淋巴细胞上几种激活标志物的过表达。它对MRL/lpr CD4 T脾细胞中的CXCR4途径产生影响。这些结果强调了CXCL12/CXCR4轴在狼疮病理生理学中的重要性。它们表明，通过中性配体LIT-927中和CXCL12可以减弱狼疮中过度活跃的淋巴细胞。这种干预方式可能代表了一种控制炎症性疾病中常见病理生理机制的新策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/8566942/ff268b49e4cc/fphar-12-752194-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/8566942/669211524ab8/fphar-12-752194-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/8566942/3275a6277e0d/fphar-12-752194-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/8566942/68a83d855f1d/fphar-12-752194-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/8566942/ff268b49e4cc/fphar-12-752194-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/8566942/669211524ab8/fphar-12-752194-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/8566942/3275a6277e0d/fphar-12-752194-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/8566942/68a83d855f1d/fphar-12-752194-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/8566942/ff268b49e4cc/fphar-12-752194-g004.jpg

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