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

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-02-06 Epub Date: 2025-01-12 DOI:10.1016/j.intimp.2025.114027

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

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引用次数: 0

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.

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阻断 CCL5/CCL7-CCR1 轴通过 NF-κB 通路调节巨噬细胞极化，从而缓解骨关节炎的进展。

目的：研究CCR1及其配体对巨噬细胞极化的影响，并评价其对软骨细胞在缓解骨关节炎进展中的作用。方法：将RAW细胞极化为M1/M2亚型，然后加入不同浓度的BX471选择性抑制CCR1。采用RT-qPCR、免疫荧光和流式细胞术检测细胞的极化情况。CCL5和CCL7基因被SiRNA沉默，并分析其在巨噬细胞极化中的作用。进一步使用巨噬细胞条件培养基刺激软骨细胞。对BX471治疗前后的内侧半月板（DMM）模型进行组织学观察。结果：我们发现阻断CCR1并沉默其配体CCL5和CCL7可降低M1巨噬细胞的极化。在机制上，我们发现阻断CCR1可以降低NF-κB通路的激活，抑制IKK、IκBα和P65的磷酸化。此外，阻断CCR1也可以减轻巨噬细胞条件培养基诱导的软骨损伤。在体内，阻断CCR1可减少M1巨噬细胞的浸润和积聚，减轻关节软骨损伤。结论：CCL5/CCL7-CCR1轴参与巨噬细胞极化，阻断其可减轻滑膜炎，缓解骨性关节炎病程。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.