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

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

doi:10.3389/fphar.2021.752194

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

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

Authors

Nicolas Schall¹, François Daubeuf^{2

3}, Claire Marsol², Patrick Gizzi³, Nelly Frossard², Dominique Bonnet², Jean-Luc Galzi¹, Sylviane Muller^{1

4

5}

Affiliations

¹ CNRS UMR7242, Biotechnology and Cell Signaling, Ecole Supérieure de Biotechnologie de Strasbourg, Strasbourg University/Strasbourg Drug Discovery and Development Institute (IMS), Strasbourg, France.
² CNRS UMR7200, Laboratoire d'innovation Thérapeutique, Faculté de Pharmacie, Strasbourg University/Strasbourg Drug Discovery and Development Institute (IMS), Strasbourg, France.
³ CNRS UMS3286, Plate-forme de Chimie Biologique Intégrative de Strasbourg, Strasbourg University/ Strasbourg Drug Discovery and Development Institute (IMS), Strasbourg, France.
⁴ Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg University, Strasbourg, France.
⁵ University of Strasbourg Institute for Advanced Study (USIAS), Strasbourg, France.

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). In vitro, 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.

Keywords: CXCL12/CXCR4 axis; MRL/lpr mouse model; inflammation; neutraligand; therapy.