炎症体
炎症
促炎细胞因子
CD36
伤口愈合
巨噬细胞
清道夫受体
医学
免疫学
受体
化学
生物化学
内科学
脂蛋白
胆固醇
体外
作者
Dongming Lv,Xiaoling Cao,Zhong Li,Yunxian Dong,Zhongye Xu,Yanchao Rong,Hailin Xu,Zhiyong Wang,Hao Yang,Rong Yin,Miao Chen,Chao Ke,Zhicheng Hu,Wuguo Deng,Bing Tang
标识
DOI:10.1016/j.xcrm.2023.101129
摘要
Moderate inflammation is essential for standard wound healing. In pathological conditions, such as diabetes, protracted and refractory wounds are associated with excessive inflammation, manifested by persistent proinflammatory macrophage states. However, the mechanisms are still unclear. Herein, we perform a metabolomic profile and find a significant phenylpyruvate accumulation in diabetic foot ulcers. Increased phenylpyruvate impairs wound healing and augments inflammatory responses, whereas reducing phenylpyruvate via dietary phenylalanine restriction relieves uncontrolled inflammation and benefits diabetic wounds. Mechanistically, phenylpyruvate is ingested into macrophages in a scavenger receptor CD36-dependent manner, binds to PPT1, and inhibits depalmitoylase activity, thus increasing palmitoylation of the NLRP3 protein. Increased NLRP3 palmitoylation is found to enhance NLRP3 protein stability, decrease lysosome degradation, and promote NLRP3 inflammasome activation and the release of inflammatory factors, such as interleukin (IL)-1β, finally triggering the proinflammatory macrophage phenotype. Our study suggests a potential strategy of targeting phenylpyruvate to prevent excessive inflammation in diabetic wounds.
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