Blocking the CCL5/CCL7-CCR1 axis regulates macrophage polarization through NF-κB pathway to alleviate the progression of osteoarthritis

Hanqing Xu; Yi He; Sheng Chen; Chen Meng; Qingyi Liu; Xiao-Jian Huang; Hong-Bo You

doi:10.1016/j.intimp.2025.114027

Blocking the CCL5/CCL7-CCR1 axis regulates macrophage polarization through NF-κB pathway to alleviate the progression of osteoarthritis

Int Immunopharmacol. 2025 Jan 12:147:114027. doi: 10.1016/j.intimp.2025.114027. Online ahead of print.

Authors

Hanqing Xu¹, Yi He², Sheng Chen¹, Chen Meng¹, Qingyi Liu¹, Xiao-Jian Huang³, Hong-Bo You⁴

Affiliations

¹ Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan City, Hubei Province, China.
² Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 1 Minde Road, Donghu, Nanchang 330006, Jiangxi, China.
³ Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan City, Hubei Province, China. Electronic address: 939251163@qq.com.
⁴ Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan City, Hubei Province, China. Electronic address: hbyou360@hotmail.com.

PMID: 39805173
DOI: 10.1016/j.intimp.2025.114027

Abstract

Objective: To study the effect of CCR1 and its ligands on macrophage polarization and evaluate its effect on chondrocytes in relieving the progression of osteoarthritis.

Methods: RAW cells were polarized to M1/M2 subtype, and then different concentrations of BX471 were added to selectively inhibit CCR1. The polarization of the cells was detected by RT-qPCR, immunofluorescence and flow cytometry. CCL5 and CCL7 genes were silenced by SiRNA and its role in macrophage polarization was analyzed. Macrophage conditioned medium was further used to stimulate chondrocytes. Histological observation was carried out on models of medial meniscus (DMM) with or without BX471 treatment.

Results: We found that blocking of CCR1 and silencing of its ligand, CCL5 and CCL7, reduced the polarization of M1 macrophages. In terms of mechanism, we found that blocking CCR1 could reduce the activation of NF-κB pathway and inhibit the phosphorylation of IKK, IκBα and P65. In addition, blocking of CCR1 could also reduce cartilage injury induced by macrophage conditioned medium. In vivo, blocking of CCR1 reduced the infiltration and accumulation of M1 macrophages and alleviated articular cartilage injury.

Conclusion: CCL5/CCL7-CCR1 axis was involved in macrophage polarization, and blocking it could reduce synovitis and alleviate the process of OA.

Keywords: CCR1; Macrophage polarization; Osteoarthritis; Synovium.