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  3. A Comparative Study of the Effects of Nine CXCR3 Antagonists on Macrophage Function and the Treatment of Acute Lung Injury

A Comparative Study of the Effects of Nine CXCR3 Antagonists on Macrophage Function and the Treatment of Acute Lung Injury

  • Front Biosci (Landmark Ed). 2025 Oct 31;30(10):45931. doi: 10.31083/FBL45931.
Mengjie Zhang 1,  Ziyu Wan 1,  Zefeng Zhu 1,  Pengbin Wang 1,  Xuan Xu 1,  Tianhao Ma 1,  Feng Qian 2,  Lexing Li 3,  Guoquan Liu 1,  Wei Gu 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, 233030 Bengbu, Anhui, China.
  • 2 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 200240 Shanghai, China.
  • 3 College of Life Science and Technology, Wuhan University of Bioengineering, 430415 Wuhan, Hubei, China.
PMID: 41198562 DOI: 10.31083/FBL45931
Abstract

Background: The C-X-C motif Chemokine Receptor 3 (CXCR3) antagonist AMG 487 has been shown to alleviate acute lung injury (ALI) in mice. Other CXCR3 antagonists, including NBI-74330, TAK-779, and SCH 546738, exhibit anti-inflammatory effects in various diseases, including apical periodontitis, arthritis, and acute respiratory distress syndrome (ARDS). However, with the exception of AMG 487, the roles of these antagonists in ALI remain poorly understood. Macrophages can differentiate into various phenotypes and play a crucial role in the progression of inflammatory and autoimmune diseases.

Methods and results: In this study, we demonstrate that the CXCR3 Agonist C-X-C motif chemokine ligand 10 (CXCL10) enhances macrophage efferocytosis and polarizes inflammatory macrophages toward the M1 phenotype, thereby exacerbating ALI in mice. Conversely, nine CXCR3 antagonists were found to inhibit macrophage efferocytosis and promote the polarization of inflammatory macrophages toward the M2 phenotype, resulting in the alleviation of ALI in mice. Subsequently, molecular docking techniques were employed to analyze interactions between nine CXCR3 antagonists and the CXCR3 protein, with the aim of screening for superior antagonist structures and designing more effective compound configurations targeting the CXCL10-CXCR3 axis. Notably, TAK-779 exhibited the most stable binding affinity to the CXCR3 protein. Furthermore, two newly modified compounds-TAK-779 from imidazolium 1 and TAK-779, 2745583-demonstrated enhanced efficacy compared to the original TAK-779 compound.

Conclusions: All nine CXCR3 antagonists were shown to influence macrophage function to varying degrees and confer protective effects against ALI. These finding suggest that comparative evaluation of CXCR3 antagonists and the discovery of novel compounds may provide new therapeutic targets for the treatment of inflammatory diseases.

Keywords

CXCL10; CXCR3; CXCR3 antagonist; TAK-779 derivative; acute lung injury; chemokine.

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