The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
University of Chinese Academy of Sciences, Beijing 100039, China; and.
J Immunol. 2019 Nov 15;203(10):2712-2723. doi: 10.4049/jimmunol.1900212. Epub 2019 Oct 9.
The inflammasomes play critical roles in numerous pathological conditions largely through IL-1β and/or IL-18. However, additional effectors have been implied from multiple studies. In this study, through two independent mass spectrometry-based secretome screening approaches, we identified galectin-3 as an effector protein of the NLRP3 inflammasome. Although the activation of AIM2 or NLRC4 inflammasome also led to galectin-3 secretion, only the NLRP3 inflammasome controlled the serum galectin-3 level under physiological condition. Mechanistically, active gasdermin D drove the nonexosomal secretion of galectin-3 through the plasma membrane pores. In vivo, high-fat diet-fed mice exhibited decreased circulating galectin-3 compared with wild-type animals. Of note, the improved insulin sensitivity in such mice was aggravated by infusion of recombinant galectin-3. Moreover, galectin-3 was essential for insulin resistance induction in mice harboring the hyperactive allele. Thus, the inflammasome-galectin-3 axis has been demonstrated as a promising target to intervene inflammasome and/or galectin-3 related diseases.
炎性小体在许多病理条件中发挥关键作用，主要通过 IL-1β 和/或 IL-18。然而，多项研究表明还存在其他效应物。在这项研究中，通过两种独立的基于质谱的分泌组筛选方法，我们鉴定出半乳糖凝集素-3 是 NLRP3 炎性小体的效应蛋白。虽然 AIM2 或 NLRC4 炎性小体的激活也导致半乳糖凝集素-3 的分泌，但只有 NLRP3 炎性小体在生理条件下控制血清半乳糖凝集素-3 水平。在机制上，活性的 GSDMD 通过质膜孔驱动半乳糖凝集素-3 的非胞吐分泌。在体内，高脂肪饮食喂养的 小鼠与野生型动物相比，循环中的半乳糖凝集素-3 减少。值得注意的是，在携带高活性 等位基因的小鼠中，输注重组半乳糖凝集素-3 加重了胰岛素敏感性的改善。此外，半乳糖凝集素-3 对于在携带高活性 等位基因的小鼠中诱导胰岛素抵抗是必需的。因此，炎性小体-半乳糖凝集素-3 轴已被证明是干预炎性小体和/或半乳糖凝集素-3 相关疾病的有前途的靶点。
