1. Mitochondrial interaction of fibrosis-protective 5-methoxy tryptophan enhances collagen uptake by macrophages
- Author
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European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Wellcome Trust, Royal Society (UK), Maassen, Sjors, Warner, Harry, Ioannidis, Melina, Jansma, Jack, Markus, Hugo, El Aidy, Sahar, Chiara, María-Dolores, Chiara, José Luis, Maierhofer, Larissa, Weavers, Helen, Van Den Boogart, Geert, European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Wellcome Trust, Royal Society (UK), Maassen, Sjors, Warner, Harry, Ioannidis, Melina, Jansma, Jack, Markus, Hugo, El Aidy, Sahar, Chiara, María-Dolores, Chiara, José Luis, Maierhofer, Larissa, Weavers, Helen, and Van Den Boogart, Geert
- Abstract
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.
- Published
- 2022