浙江大学医学院王迪团队近期取得重要工作进展，他们研究提出，Gasdermin D介导的代谢相互作用促进组织修复。相关研究成果2024年9月11日在线发表于《自然》杂志上。

据介绍，建立早期促再生生态位对组织再生至关重要。GSDMD依赖性焦亡解释了各种损伤后炎性细胞因子的释放。然而，人们对它在组织再生和稳态维持中的作用知之甚少。

研究人员发现巨噬细胞GSDMD缺乏会延迟组织恢复，对局部炎症环境或裂解性焦亡过程几乎没有影响。过度活化巨噬细胞的代谢产物分泌组分析揭示了GSDMD的非规范代谢产物分泌功能。研究人员进一步确定11,12-环氧二十碳三烯酸（11,12-EET）是一种生物活性促愈合的氧脂质，由过度活跃的巨噬细胞以GSDMD依赖的方式分泌。

事实上，通过直接补充或删除其水解酶Ephx2来积累11,12-EET加速了肌肉再生。Ephx2水平在衰老的肌肉中积累。连续11,12-EET治疗使衰老的肌肉恢复活力。从机制上讲，11,12-EET通过调节FGF液-液相分离来放大FGF-FGFR信号，从而促进肌肉干细胞（MuSC）的活化和增殖。

总之，这一研究描绘了巨噬细胞和MuSC之间由GSDMD引导的代谢产物相互作用，该相互作用控制着修复过程，为受伤或衰老组织的再生提供了新的治疗见解。

附：英文原文

Title: Gasdermin D-mediated metabolic crosstalk promotes tissue repair

Author: Chi, Zhexu, Chen, Sheng, Yang, Dehang, Cui, Wenyu, Lu, Yang, Wang, Zhen, Li, Mobai, Yu, Weiwei, Zhang, Jian, Jiang, Yu, Sun, Ruya, Yu, Qianzhou, Hu, Tianyi, Lu, Xiaoyang, Deng, Qiqi, Yang, Yidong, Zhao, Tianming, Chang, Mengfei, Li, Yuying, Zhang, Xue, Shang, Min, Xiao, Qian, Ding, Kefeng, Wang, Di

Issue&Volume: 2024-09-11

Abstract: The establishment of an early pro-regenerative niche is crucial for tissue regeneration1,2. Gasdermin D (GSDMD)-dependent pyroptosis accounts for the release of inflammatory cytokines upon various insults3-5. However, little is known about its role in tissue regeneration followed by homeostatic maintenance. Here, we show that macrophage GSDMD deficiency delayed tissue recovery, with little impact on the local inflammatory milieu or the lytic pyroptosis process. Metabolite secretome profiling of hyperactivated macrophages unveiled the non-canonical metabolite-secreting function of GSDMD. And we further identified 11,12-epoxyeicosatrienoic acid (11,12-EET) as a bioactive pro-healing oxylipin, secreted from hyperactive macrophages in a GSDMD-dependent manner. Indeed, accumulation of 11,12-EET by direct supplementation or deletion of its hydrolytic enzyme Ephx2 accelerated muscle regeneration. We further demonstrated that the Ephx2 level accumulated within aged muscle. And consecutive 11,12-EET treatment rejuvenated aged muscle. Mechanistically, 11,12-EET amplifies FGF-FGFR signaling by modulating FGF liquid-liquid phase separation, hence boosting the activation and proliferation of muscle stem cells (MuSCs). These data depict a GSDMD-guided metabolite crosstalk between macrophages and MuSCs that governs the repair process, which offers new therapeutic insights for the regeneration of injured or aged tissues.

DOI: 10.1038/s41586-024-08022-7

Source: https://www.nature.com/articles/s41586-024-08022-7