Spatiotemporal orchestration of macrophage activation trajectories by Vγ4 T cells during skin wound healing
Wengang Hu,
Xiaorong Zhang,
Zhongyang Liu,
Jiacai Yang,
Hao Sheng,
Zhihui Liu,
Cheng Chen,
Ruoyu Shang,
Yunxia Chen,
Yifei Lu,
Xiaohong Hu,
Yong Huang,
Wenjing Yin,
Xin Cai,
Dejiang Fan,
Lingfeng Yan,
Jianlei Hao,
Gaoxing Luo,
Weifeng He
Affiliations
Wengang Hu
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Xiaorong Zhang
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Zhongyang Liu
Department of Plastic Surgery, the First Affiliated Hospital, Zhengzhou University, Henan, China
Jiacai Yang
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Hao Sheng
Urology Department, the Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
Zhihui Liu
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Cheng Chen
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Ruoyu Shang
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Yunxia Chen
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Yifei Lu
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Xiaohong Hu
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Yong Huang
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Wenjing Yin
Academy of Biological Engineering, Chongqing University, Chongqing, China
Xin Cai
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Dejiang Fan
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Lingfeng Yan
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China
Jianlei Hao
Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000 Guangdong, China; The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou 510632, Guangdong, China
Gaoxing Luo
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China; Corresponding author
Weifeng He
State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing 400038, China; Corresponding author
Summary: Dysregulated macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes underlies impaired cutaneous wound healing. This study reveals Vγ4+ γδ T cells spatiotemporally calibrate macrophage trajectories during skin repair via sophisticated interferon-γ (IFN-γ) conditioning across multiple interconnected tissues. Locally within wound beds, infiltrating Vγ4+ γδ T cells directly potentiate M1 activation and suppress M2 polarization thereby prolonging local inflammation. In draining lymph nodes, infiltrated Vγ4+ γδ T cells expand populations of IFN-γ-competent lymphocytes which disseminate systemically and infiltrate into wound tissues, further enforcing M1 macrophages programming. Moreover, Vγ4+γδ T cells flushed into bone marrow stimulate increased IFN-γ production, which elevates the output of pro-inflammatory Ly6C+monocytes. Mobilization of these monocytes continually replenishes the M1 macrophage pool in wounds, preventing phenotypic conversion to M2 activation. Thus, multi-axis coordination of macrophage activation trajectories by trafficking Vγ4+ γδ T cells provides a sophisticated immunological mechanism regulating inflammation timing and resolution during skin repair.
