巨噬细胞的代谢支持维持结肠上皮稳态。

Cell metabolism Pub Date : 2023-11-07 Epub Date: 2023-10-06 DOI:10.1016/j.cmet.2023.09.010
Stephanie Deborah Fritsch, Nyamdelger Sukhbaatar, Karine Gonzales, Alishan Sahu, Loan Tran, Andrea Vogel, Mario Mazic, Jayne Louise Wilson, Stephan Forisch, Hannah Mayr, Raimund Oberle, Jakob Weiszmann, Martin Brenner, Roeland Vanhoutte, Melanie Hofmann, Sini Pirnes-Karhu, Christoph Magnes, Torben Kühnast, Wolfram Weckwerth, Christoph Bock, Kristaps Klavins, Markus Hengstschläger, Christine Moissl-Eichinger, Gernot Schabbauer, Gerda Egger, Eija Pirinen, Steven H L Verhelst, Thomas Weichhart
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引用次数: 2

摘要

肠上皮具有高周转率,并通过肠隐窝细胞的增殖不断更新自身,这依赖于来自微环境的特征不充分的信号。在这里,我们发现结肠巨噬细胞直接位于小鼠的上皮隐窝细胞附近,在那里它们以mTORC1依赖的方式代谢支持上皮细胞增殖。具体而言,巨噬细胞中结节性硬化复合物2(Tsc2)的缺失激活了mTORC1信号传导,该信号传导可防止结肠炎诱导的肠道损伤,并诱导多胺亚精胺和精胺的合成。上皮细胞摄入这些多胺并重新连接其细胞代谢以优化增殖和防御。值得注意的是,精胺直接刺激结肠上皮细胞和结肠类器官的增殖。巨噬细胞中多胺产生的遗传干扰改变了结肠中的整体多胺水平,并改变了上皮细胞的增殖。我们的研究结果表明,巨噬细胞充当“共生体”,提供代谢支持,促进结肠上皮的有效自我更新。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Metabolic support by macrophages sustains colonic epithelial homeostasis.

The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently characterized signals from the microenvironment. Here, we showed that colonic macrophages were located directly adjacent to epithelial crypt cells in mice, where they metabolically supported epithelial cell proliferation in an mTORC1-dependent manner. Specifically, deletion of tuberous sclerosis complex 2 (Tsc2) in macrophages activated mTORC1 signaling that protected against colitis-induced intestinal damage and induced the synthesis of the polyamines spermidine and spermine. Epithelial cells ingested these polyamines and rewired their cellular metabolism to optimize proliferation and defense. Notably, spermine directly stimulated proliferation of colon epithelial cells and colon organoids. Genetic interference with polyamine production in macrophages altered global polyamine levels in the colon and modified epithelial cell proliferation. Our results suggest that macrophages act as "commensals" that provide metabolic support to promote efficient self-renewal of the colon epithelium.

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