Mitochondrial interaction of fibrosis-protective 5-methoxy tryptophan enhances collagen uptake by macrophages.

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. Schematic overview of the effects of 5-MTP on human monocyte derived macrophages. 5-MTP promotes mitochondrial fusion, protecting against oxidative stress, and increases glucose uptake which drive collagen uptake. However, IDO is able to negate any anti-inflammatory effects by breaking down 5-MTP. [Display omitted] • 5-MTP increases collagen uptake in macrophages. • 5-MTP protects against mitochondrial oxidative stress. • Macrophages increase their sugar metabolism in the presence of 5-MTP. • Macrophages are able to breakdown 5-MTP via indoleamine oxygenase (IDO). [ABSTRACT FROM AUTHOR]