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Tryptophan metabolites kynurenine and serotonin regulate fibroblast activation and fibrosis

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Abstract

Fibrosis is a pathological form of aberrant tissue repair, the complications of which account for nearly half of all deaths in the industrialized world. All tissues are susceptible to fibrosis under particular pathological sets of conditions. Though each type of fibrosis has characteristics and hallmarks specific to that particular condition, there appear to be common factors underlying fibrotic diseases. One of these ubiquitous factors is the paradigm of the activated myofibroblast in the promotion of fibrotic phenotypes. Recent research has implicated metabolic byproducts of the amino acid tryptophan, namely serotonin and kynurenines, in the pathology or potential pharmacologic therapy of fibrosis, in part through their effects on development of myofibroblast phenotypes. Here, we review literature underlying what is known mechanistically about the effects of these compounds and their respective pathways on fibrosis. Pharmacologic administration of kynurenine improves scarring outcomes in vivo likely not only through its well-characterized immunosuppressive properties but also via its demonstrated antagonism of fibroblast activation and of collagen deposition. In contrast, serotonin directly promotes activation of fibroblasts via activation of canonical TGF-β signaling, and overstimulation with serotonin leads to fibrotic outcomes in vivo. Recently discovered feedback inhibition between serotonin and kynurenine pathways also reveals more information about the cellular physiology of tryptophan metabolism and may also underlie possible paradigms for anti-fibrotic therapy. Together, understanding of the effects of tryptophan metabolism on modulation of fibrosis may lead to the development of new therapeutic avenues for treatment through exploitation of these effects.

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Funding

This work was funded by a National Institutes of Health Award (NIH R01GM85456) to Tanja Dominko and a National Science Foundation Integrative Graduate Education and Research Traineeship (Grant number DGE 1144804) awarded to David Dolivo.

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  1. Biology and Biotechnology Department, Worcester Polytechnic Institute, 100 Institute Road, Worcester, MA, 01609, USA

    David M. Dolivo, Sara A. Larson & Tanja Dominko

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  1. David M. Dolivo
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  2. Sara A. Larson
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Correspondence to Tanja Dominko.

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Dolivo, D.M., Larson, S.A. & Dominko, T. Tryptophan metabolites kynurenine and serotonin regulate fibroblast activation and fibrosis. Cell. Mol. Life Sci. 75, 3663–3681 (2018). https://doi.org/10.1007/s00018-018-2880-2

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