微泡
巨噬细胞极化
成纤维细胞
伤口愈合
巨噬细胞
炎症
细胞生物学
免疫系统
真皮成纤维细胞
M2巨噬细胞
免疫学
生物
癌症研究
小RNA
细胞培养
体外
生物化学
遗传学
基因
作者
Cheng Chen,Jiacai Yang,Ruoyu Shang,Yuanyang Tang,Xin Cai,Weifeng He,Zhihui Liu,Wengang Hu,Weiguang Zhang,Xiaorong Zhang,Yong Huang,Xiaohong Hu,Wenjing Yin,Qudong Lu,Hao Sheng,Dejiang Fan,Zhenyu Ju,Gaoxing Luo,Weifeng He
标识
DOI:10.1016/j.jid.2024.05.007
摘要
Macrophages undertake pivotal yet dichotomous functions during skin wound healing, mediating both early proinflammatory immune activation and late anti-inflammatory tissue remodeling processes. The timely phenotypic transition of macrophages from inflammatory M1 to proresolving M2 activation states is essential for efficient healing. However, the endogenous mechanisms calibrating macrophage polarization in accordance with the evolving tissue milieu remain undefined. In this study, we reveal an indispensable immunomodulatory role for fibroblast-secreted exosomes in directing macrophage activation dynamics. Fibroblast-derived exosomes permitted spatiotemporal coordination of macrophage phenotypes independent of direct intercellular contact. Exosomes enhanced macrophage sensitivity to both M1 and M2 polarizing stimuli, yet they also accelerated timely switching from M1 to M2 phenotypes. Exosome inhibition dysregulated macrophage responses, resulting in aberrant inflammation and impaired healing, whereas provision of exogenous fibroblast-derived exosomes corrected defects. Topical application of fibroblast-derived exosomes onto chronic diabetic wounds normalized dysregulated macrophage activation to resolve inflammation and restore productive healing. Our findings elucidate fibroblast-secreted exosomes as remote programmers of macrophage polarization that calibrate immunological transitions essential for tissue repair. Harnessing exosomes represents a previously unreported approach to steer productive macrophage activation states with immense therapeutic potential for promoting healing in chronic inflammatory disorders.
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