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

Sjors Maassen, Harry Warner, Melina Ioannidis, Jack Jansma, Hugo Markus, Sahar El Aidy, María-Dolores Chiara, Jose Luis Chiara, Larissa Maierhofer, Helen Weavers, Geert van den Bogaart*

*Bijbehorende auteur voor dit werk

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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.

Originele taal-2English
Artikelnummer202206235
Pagina's (van-tot)287-297
Aantal pagina's11
TijdschriftFree Radical Biology and Medicine
Volume188
DOI's
StatusPublished - aug-2022

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