Control of Tissue Fibrosis by 5-Methoxytryptophan, an Innate Anti-Inflammatory Metabolite.

Kenneth K Wu

doi:10.3389/fphar.2021.759199

Abstract

Tissue fibrosis causes debilitating human diseases such as liver cirrhosis, heart failure, chronic kidney disease and pulmonary insufficiency. It is a dynamic process orchestrated by specific subsets of monocyte-macrophages, fibroblasts, pericytes and hepatic stellate cells. Fibrosis is linked to tissue inflammation. Pro-inflammatory macrophages promote fibrosis by driving myofibroblast differentiation and macrophage myofibroblast transition. Myofibroblasts express α-smooth muscle cell actin (α-SMA) and secrete extracellular matrix (ECM) proteins notably collagen I and III. Deposition of ECM proteins at injury sites and interstitial tissues distorts normal structure and impairs vital functions. Despite advances in the mechanisms of fibrosis at cellular, molecular and genetic levels, prevention and treatment of fibrotic diseases remain poorly developed. Recent reports suggest that 5-methoxytryptophan (5-MTP) is effective in attenuating injury-induced liver, kidney, cardiac and pulmonary fibrosis. It inhibits macrophage activation and blocks fibroblast differentiation to myofibroblasts. Furthermore, it inhibits hepatic stellate cell differentiation into myofibroblasts. As 5-MTP is an endogenous molecule derived from tryptophan catabolism via tryptophan hydroxylase pathway, it is well-suited as a lead compound for developing new anti-fibrotic drugs. This article provides an overview of 5-MTP synthesis, and a critical review of its anti-fibrotic activities. Its mechanisms of actions and potential therapeutic value will be discussed.

Highlights

Fibrous deposition at the injured tissue is a fundamental repair process (Eming et al, 2014)
In vitro experiments provide evidence to support the observation that 5-MTP inhibits fibroblast differentiation to myofibroblasts and reduces fibroblast migration by blocking TGFβ signaling pathway (Fang et al, 2020). These findings suggest that 5-MTP is effective in attenuating pulmonary fibrosis due to external injury
Genetic deletion of Mapk14 blocks fibroblast differentiation to myofibroblasts in a murine cardiac injury model (Ma et al, 1999). These results suggest that p38 MAPK is a major signaling molecule of fibroblast differentiation and activation and plays a central role in in pathological fibrosis

Summary

Introduction

Fibrous deposition at the injured tissue is a fundamental repair process (Eming et al, 2014). Uncontrolled fibrous deposition at the injured and normal interstitial tissues leads to structural remodeling and functional defects (Henderson et al, 2020). ECM proteins deposit at the injured sites and the adjacent interstitial space and distort normal structure and impair organ function. Macrophages release myriad pro-inflammatory cytokines and chemokines to elicit inflammatory responses and cause tissue damage. They crosstalk with fibroblasts and promote fibroblasts differentiation to myofibroblasts (Karlmark et al, 2009; Murray et al, 2011; Tang et al, 2019; Zhang F. et al, 2020). Macrophages may be transdifferentiated into myofibroblasts through macrophage myofibroblast transition (MMT) (Murray et al, 2011)

Objectives

Findings

Conclusion