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Mitochondrial interaction of fibrosis-protective 5-methoxy tryptophan enhances collagen uptake by macrophages
Sjors Maassen1, Harry Warner1, Melina Ioannidis1
1Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, 050, the Netherlands.
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.
Insights
5-methoxy tryptophan (5-MTP) protects against fibrosis by altering macrophage mitochondria and metabolism. This fibrosis-protective metabolite increases collagen uptake in macrophages, but is degraded during pathogenic stimulation.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- 5-methoxy tryptophan (5-MTP) is an anti-fibrotic metabolite found in human blood.
- Its role in fibrotic kidney disease progression is known, but the underlying mechanism remains unclear.
- Understanding 5-MTP's cellular effects is crucial for developing anti-fibrotic therapies.
Purpose of the Study:
- To investigate the effects of 5-methoxy tryptophan (5-MTP) on mitochondria and metabolism in human macrophages.
- To elucidate the mechanism by which 5-MTP influences macrophage function and collagen uptake.
- To determine the impact of pathogenic stimulation on 5-MTP's effects.
Main Methods:
- Microscopy and functional assays were used to analyze mitochondrial changes in macrophages.
- Metabolic alterations, including acyl-carnitine import and glucose uptake, were assessed.
- Collagen endocytosis by macrophages was measured.
- The role of indole-amine oxygenase-1 (IDO-1) in 5-MTP degradation was investigated.
Main Results:
- 5-MTP increased mitochondrial membrane rigidity and branching, enhancing protection against oxidation.
- Macrophages altered metabolism by reducing acyl-carnitine import and increasing glucose uptake.
- 5-MTP enhanced collagen endocytosis by macrophages, linked to metabolic changes.
- Pathogenic stimulation led to 5-MTP degradation via induced IDO-1 expression, negating its effects.
Conclusions:
- 5-methoxy tryptophan (5-MTP) is a fibrosis-protective metabolite that modulates macrophage mitochondrial properties and metabolism.
- In the absence of pathogenic stimuli, 5-MTP promotes collagen uptake by anti-inflammatory macrophages.
- IDO-1-mediated degradation prevents 5-MTP's anti-fibrotic effects during pathogenic stimulation.
