Spatiotemporal orchestration of macrophage activation trajectories by Vγ4 T cells during skin wound healing

• DOI: 10.1016/j.isci.2024.109545
• Publication Date: 2024-03-22T12:12:30Z
• Authors: 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
• Keywords: Macrophage polarization; Orchestration; M2 Macrophage

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.