Luo Zucheng, Zheng Shaoluan, Hu Zhichao, Li Pengfei, Zeng Junhao, Lu Yao, Ali Mohyeddin, Chen Zijian, Wang Qi, Qi Fazhi
Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Plastic and Reconstructive Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China.
Free Radic Biol Med. 2025 Jun;233:302-316. doi: 10.1016/j.freeradbiomed.2025.04.007. Epub 2025 Apr 3.
Diabetic wound healing presents a significant clinical challenge due to disrupted neuro-immune interactions. This study identifies the α7 nicotinic acetylcholine receptor (α7nAChR) as a key regulator of wound repair by linking cholinergic signaling to macrophage reprogramming. GEO analysis of diabetic foot ulcer (DFU) microenvironments revealed neuronal loss, M1 macrophage dominance, and chronic inflammation, all driven by impaired acetylcholine (ACh) secretion and α7nAChR inactivation. Mechanistically, taurine (TA) restored PC12 cell function under high glucose conditions by activating AMPK, alleviating oxidative and endoplasmic reticulum stress, and promoting ACh production. ACh activated macrophage α7nAChR, modulating M1/M2 polarization through JAK2/STAT3 activation and NF-κB suppression. To enhance TA bioavailability, ultrasound-responsive Ccr2-targeted TA nanoparticles (Ccr2@TA@LNP) were developed for site-specific delivery via Ccl2/Ccr2 chemotaxis. In diabetic neuropathy (DPN) mice, Ccr2@TA@LNP accelerated wound healing by increasing ACh levels, enhancing α7nAChR/CD206 expression, and reducing Ccl2-mediated inflammation. By integrating neuroprotection, macrophage reprogramming, and targeted nanotherapy, this study highlights TA as a multi-target agent that restores neuro-immune balance through the AMPK/α7nAChR/JAK2-STAT3 axis, offering a novel therapeutic strategy for diabetic wound treatment.
由于神经 - 免疫相互作用受到破坏，糖尿病伤口愈合面临重大临床挑战。本研究通过将胆碱能信号与巨噬细胞重编程联系起来，确定α7烟碱型乙酰胆碱受体（α7nAChR）是伤口修复的关键调节因子。对糖尿病足溃疡（DFU）微环境的基因表达综合数据库（GEO）分析显示，神经元丧失、M1巨噬细胞占主导以及慢性炎症，这些均由乙酰胆碱（ACh）分泌受损和α7nAChR失活所驱动。机制上，牛磺酸（TA）在高糖条件下通过激活AMPK、减轻氧化应激和内质网应激以及促进ACh产生来恢复PC12细胞功能。ACh激活巨噬细胞α7nAChR，通过JAK2/STAT3激活和NF-κB抑制来调节M1/M2极化。为提高TA的生物利用度，开发了超声响应性靶向趋化因子受体2（Ccr2）的TA纳米颗粒（Ccr2@TA@LNP），通过Ccl2/Ccr2趋化作用进行位点特异性递送。在糖尿病性神经病变（DPN）小鼠中，Ccr2@TA@LNP通过增加ACh水平、增强α7nAChR/CD206表达以及减少Ccl2介导的炎症来加速伤口愈合。通过整合神经保护、巨噬细胞重编程和靶向纳米治疗，本研究强调TA作为一种多靶点药物，通过AMPK/α7nAChR/JAK2 - STAT3轴恢复神经 - 免疫平衡，为糖尿病伤口治疗提供了一种新的治疗策略。
