CXCL16/CXCR6/TGF-β Feedback Loop Between M-MDSCs and Treg Inhibits Anti-Bacterial Immunity During Biofilm Infection,Advanced Science

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CXCL16/CXCR6/TGF-β Feedback Loop Between M-MDSCs and Treg Inhibits Anti-Bacterial Immunity During Biofilm Infection
Advanced Science ( IF 14.3 ) Pub Date : 2024-12-24 , DOI: 10.1002/advs.202409537
Xiaoyu Wu _{1,

2,

3} , Baiqi Pan _{1,

2,

3} , Chenghan Chu _{1,

2,

3} , Yangchun Zhang _{4,

5} , Jinjin Ma _{6,

7} , Yang Xing _{1,

2,

3} , Yuanchen Ma ₈ , Wengang Zhu ₉ , Huan Zhong ₁₀ , Aerman Alimu _{1,

2,

3} , Guanming Zhou ₁₁ , Shuying Liu ₁₂ , Weishen Chen _{1,

2,

3} , Xiang Li _{2,

13} , Sheng Puyi _{1,

2,

3}

Affiliation

Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Guangdong Provincial Clinical Research Center for Orthopedic Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou, Guangdong, 510080, China.
Department of Orthopedics, The People's Hospital of Baoan Shenzhen, Shenzhen, Guangdong, 518101, China.
Department of Orthopedics, The Second Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, 518101, China.
Technology School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510640, China.
Shien-ming Wu School of Intelligent Engineering, South China University of Technology, Guangzhou, Guangdong, 510640, China.
Department of Orthopedics, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 519041, China.
Department of Joint Orthopedics, Yuebei People's Hospital, Shaoguan, Guangdong, 512099, China.
Department of Joint Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524002, China.
Department of Orthopedics, Foshan Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, 528051, China.
Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.

Staphylococcus aureus (S. aureus) is a leading cause of Periprosthetic joint infection (PJI), a severe complication after joint arthroplasty. Immunosuppression is a major factor contributing to the infection chronicity of S. aureus PJI, posing significant treatment challenges. This study investigates the relationship between the immunosuppressive biofilm milieu and S. aureus PJI outcomes in both discovery and validation cohorts. This scRNA-seq analysis of synovium from PJI patients reveals an expansion and heightened activity of monocyte-related myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Treg). Importantly, CXCL16 is significantly upregulated in M-MDSCs, with its corresponding CXCR6 receptor also elevated on Treg. M-MDSCs recruit Treg and enhance its activity via CXCL16-CXCR6 interactions, while Treg secretes TGF-β, inducing M-MDSCs proliferation and immunosuppressive activity. Interfering with this cross-talk in vivo using Treg-specific CXCR6 knockout PJI mouse model reduces M-MDSCs/Treg-mediated immunosuppression and alleviates bacterial burden. Immunohistochemistry and recurrence analysis show that PJI patients with CXCR6^high synovium have poor prognosis. This findings highlight the critical role of CXCR6 in Treg in orchestrating an immunosuppressive microenvironment and biofilm persistence during PJI, offering potential targets for therapeutic intervention.

中文翻译：

m-MDSCs 和 Treg 之间的 CXCL16/CXCR6/TGF-β 反馈回路抑制生物膜感染期间的抗菌免疫

金黄色葡萄球菌（S. aureus） 是关节置换术后严重并发症人工体周围关节感染（PJI）的主要原因。免疫抑制是导致金黄色葡萄球菌 PJI 感染慢性的主要因素，带来了重大的治疗挑战。本研究调查了免疫抑制生物膜环境与发现和验证队列中金黄色葡萄球菌 PJI 结果之间的关系。对 PJI 患者滑膜的 scRNA-seq 分析揭示了单核细胞相关髓源性抑制细胞（M-MDSC）和调节性 T 细胞（Treg）的扩增和活性升高。重要的是，CXCL16 在 M-MDSC 中显著上调，其相应的 CXCR6 受体在 Treg 上也升高。M-MDSCs 通过 CXCL16-CXCR6 相互作用募集 Treg 并增强其活性，而 Treg 分泌 TGF-β，诱导 M-MDSCs 增殖和免疫抑制活性。使用 Treg 特异性 CXCR6 敲除 PJI 小鼠模型在体内干扰这种串扰可减少 M-MDSC/Treg 介导的免疫抑制并减轻细菌负荷。免疫组化和复发分析显示 CXCR6^高滑膜的 PJI 患者预后不良。这一发现强调了 CXCR6 在 Treg 中在 PJI 期间协调免疫抑制微环境和生物膜持久性中的关键作用，为治疗干预提供了潜在的靶点。

更新日期：2024-12-24

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