Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, 050, the Netherlands.
Department of Host-Microbe Interactions, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, 050, the Netherlands.
Free Radic Biol Med. 2022 Aug 1;188:287-297. doi: 10.1016/j.freeradbiomed.2022.06.235. Epub 2022 Jun 23.
5-methoxy tryptophan (5-MTP) is an anti-fibrotic metabolite made by fibroblasts and epithelial cells, present in a micromolar concentrations in human blood, and is associated with the progression of fibrotic kidney disease, but the mechanism is unclear. Here, we show by microscopy and functional assays that 5-MTP influences mitochondria in human peripheral blood monocyte-derived macrophages. As a result, the mitochondrial membranes are more rigid, more branched, and are protected against oxidation. The macrophages also change their metabolism by reducing mitochondrial import of acyl-carnitines, intermediates of fatty acid metabolism, driving glucose import. Moreover, 5-MTP increases the endocytosis of collagen by macrophages, and experiments with inhibition of glucose uptake showed that this is a direct result of their altered metabolism. However, 5-MTP does not affect the macrophages following pathogenic stimulation, due to 5-MTP degradation by induced expression of indole-amine oxygenase-1 (IDO-1). Thus, 5-MTP is a fibrosis-protective metabolite that, in absence of pathogenic stimulation, promotes collagen uptake by anti-inflammatory macrophages by altering the physicochemical properties of their mitochondrial membranes.
5-甲氧基色氨酸（5-MTP）是成纤维细胞和上皮细胞产生的抗纤维化代谢物，在人血液中以微摩尔浓度存在，与纤维化肾病的进展有关，但机制尚不清楚。在这里，我们通过显微镜和功能分析表明，5-MTP 影响人外周血单核细胞衍生的巨噬细胞中的线粒体。结果是，线粒体膜更硬、更分支，并能抵抗氧化。巨噬细胞还通过减少脂肪酸代谢中间产物酰基辅酶 A 的线粒体摄取来改变其代谢，从而促进葡萄糖摄取。此外，5-MTP 增加了巨噬细胞对胶原蛋白的内吞作用，并且葡萄糖摄取抑制实验表明，这是其代谢改变的直接结果。然而，由于诱导表达吲哚胺 2,3-双加氧酶-1（IDO-1）导致 5-MTP 降解，因此 5-MTP 不会影响受到致病刺激的巨噬细胞。因此，5-MTP 是一种纤维化保护代谢物，在没有致病刺激的情况下，通过改变其线粒体膜的物理化学性质，促进抗炎性巨噬细胞吸收胶原蛋白。
