Low-intensity stimulation drives macrophage efferocytosis via ACSL4 lipid remodeling and CCL9-CCR1 signaling for tendon-bone healing.

Yao, Juncheng; Wu, Yuhao; Wang, Xuan; Zhang, Jiexin; Shao, Yan; Chen, Huabin; Zhang, Haiyan; Li, Haobin et al. · Sci Adv · 2026

basic_science · Level V

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Abstract

The mechanisms underlying exercise rehabilitation-induced tendon-bone healing remain unclear. Using a mouse model of anterior cruciate ligament reconstruction, we found that low-intensity mechanical stimulation promoted macrophage M2 polarization, phagocytosis, and efferocytosis at the tendon-bone interface via acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid metabolism reprogramming. <i>Acsl4</i> silencing reduced fatty acid oxidation and efferocytosis, impairing exercise rehabilitation-induced tendon-bone healing. Notably, the CCL9-CCR1 axis contributed to bone marrow stromal cell homing following macrophage efferocytosis. In addition, engineered CCL9-expressing exosomes accelerated tendon-bone repair.

Medical subject headings