MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.
Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, 310058, China.
Small. 2021 Apr;17(17):e2006992. doi: 10.1002/smll.202006992. Epub 2021 Mar 14.
Cellular metabolism plays a major role in the regulation of inflammation. The inflammatory macrophages undergo a wide-range of metabolic rewriting due to the production of significant amount of itaconate metabolite from cis-aconitate in the tricarboxylic acid cycle. This itaconate molecule has been recently described as a promising immunoregulator. However, its function and mode of action on macrophages and tissue repair and regeneration are yet unclear. Herein, the itaconate-derivative dimethyl itaconate (DMI) suppresses the IL-23/IL-17 inflammatory axis-associated genes and promotes antioxidant nuclear factor erythroid 2-related factor 2 target genes. The poly-ε-caprolactone (PCL)/DMI nanofibers implanted in mice initially maintain inflammation by suppressing anti-inflammatory activity and particular inflammation, while at later stage promotes anti-inflammatory activity for an appropriate tissue repair. Furthermore, the PCL/DMI nanofiber patches show an excellent myocardial protection by reducing infarct area and improving ventricular function via time-dependent regulation of myocardium-associated genes. This study unveils potential DMI macrophage modulatory functions in tissue microenvironment and macrophages rewriting for proper tissue repair.
细胞代谢在炎症调控中起着主要作用。由于顺乌头酸在三羧酸循环中产生大量的衣康酸代谢物，炎性巨噬细胞经历了广泛的代谢重写。这种衣康酸分子最近被描述为一种有前途的免疫调节剂。然而，其在巨噬细胞和组织修复和再生中的功能和作用模式尚不清楚。在此，衣康酸衍生物二甲基衣康酸（DMI）抑制 IL-23/IL-17 炎症轴相关基因，并促进抗氧化核因子红细胞 2 相关因子 2 靶基因。植入小鼠体内的聚己内酯（PCL）/DMI 纳米纤维最初通过抑制抗炎活性和特定炎症来维持炎症，而在后期则通过适当的组织修复来促进抗炎活性。此外，PCL/DMI 纳米纤维贴片通过时间依赖性调节心肌相关基因，减少梗死面积和改善心室功能，从而实现出色的心肌保护作用。这项研究揭示了 DMI 巨噬细胞在组织微环境和巨噬细胞重写中对适当组织修复的潜在调节功能。
