Ongoing Clinical Trials in Aging-Related Tissue Fibrosis and New Findings Related to AhR Pathways

Abstract

Fibrosis is a pathological manifestation of wound healing that replaces dead/damaged tissue with collagen-rich scar tissue to maintain homeostasis, and complications from fibrosis contribute to nearly half of all deaths in the industrialized world. Ageing is closely associated with a progressive decline in organ function, and the prevalence of tissue fibrosis dramatically increases with age. Despite the heavy clinical and economic burden of organ fibrosis as the population ages, to date, there is a paucity of therapeutic strategies that are specifically designed to slow fibrosis. Aryl hydrocarbon receptor (AhR) is an environment-sensing transcription factor that exacerbates aging phenotypes in different tissues that has been brought back into the spotlight again with economic development since AhR could interact with persistent organic pollutants derived from incomplete waste combustion. In addition, gut microbiota dysbiosis plays a pivotal role in the pathogenesis of numerous diseases, and microbiota-associated tryptophan metabolites are dedicated contributors to fibrogenesis by acting as AhR ligands. Therefore, a better understanding of the effects of tryptophan metabolites on fibrosis modulation through AhR may facilitate the exploitation of new therapeutic avenues for patients with organ fibrosis. In this review, we primarily focus on how tryptophan-derived metabolites are involved in renal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis and cardiac fibrosis. Moreover, a series of ongoing clinical trials are highlighted.

Keywords: aging; aryl hydrocarbon receptor; fibrosis; gut microbiota; metabolites; tryptophan.

Figure 1.

Schematic representation of the effect of tryptophan metabolism in age-related tissue fibrosis through AhR. Tryptophan is mainly metabolized through three pathways in the host and gut microbiota: the kynurenine pathway, serotonin pathway and indole pathway. The endogenous ligands for AhR that are surrounded in blue, including FICZ, kynurenine, kynurenic acid, xanthurenic acid, cinnabarinic acid, 5-HTP, serotonin, 5-HIAA, indole-3-pyruvate, indole-3-lactic acid, indole-3-propionic acid, indole acetic acid, 3-methylindole, tryptamine, indole-3-aldehyde, indole and indoxyl sulfate, may modulate fibrosis progression after binding with AhR. AAA-ATs: aromatic amino acid aminotransferases; AA-DC: aromatic amino acid decarboxylase; AA-NAT: arylalkylamine N-acetyltransferase; CYP2E1: cytochrome P450 2E1; FICZ: 6-formylindolo[3,2-b]carbazole; HAAO: 3-hydroxyanthranilic acid oxygenase; 5-HIAA: 5-hydroxy- indole-3-acetic acid; HIOMT: hydroxyindole O-methyltransferase; 5-HTP: 5-hydroxy-tryptophan; 5-MTP: 5-methoxy-tryptophan; IDO: indoleamine 2,3-dioxygenase; KAT: kynurenine aminotransferase; KMO: kynurenine 3-monooxygenase; KYNU: kynureninase; SULT1A1: sulfotransferase 1A1; TDO: tryptophan 2,3-dioxygenase; THP: tryptophan hydroxylase; Try: tryptophan.

Figure 2.

The crosstalk among AhR and other signalling pathways in tissue fibrosis. Both L-Kyn and KynA can activate AhR, and AhR is translocated to the nucleus upon interaction with a ligand, leading to AhR-sensitive transcription and fibrosis development. In addition to canonical AhR signalling, AhR also interacts with other pathways. TGF-β/Smad and Wnt/β-catenin signalling are other core pathways of fibrosis progression that play pivotal roles in renal fibrosis, idiopathic pulmonary fibrosis, hepatic fibrosis and cardiac fibrosis. AhR not only attenuates lung fibrosis by inducing Smad4 degradation in the proteasome but also alleviates hepatic fibrosis by disrupting the interaction of Smad3 and β-catenin. GSK3β is an inhibitor of β-catenin, and AhR may also inhibit lung fibrosis by maintaining GSK3β in an active form. Serotonin is a dedicated contributor to cardiac fibrosis and pulmonary fibrosis by activating the TGF-β signalling pathway. Moreover, it also enhances β-catenin signalling by inhibiting GSK3β. Inflammation also contributes greatly to fibrogenesis, and AhR activated by FICZ improves acute kidney injury by inhibiting NF-κB. Furthermore, AhR has been proven to suppress fibrosis by activating MMP-1/MMP-3 in fibroblasts, but whether it has a similar effect on ageing-related fibrosis remains to be determined. ARNT: aryl hydrocarbon receptor nuclear translocator; DRE: dioxin response element; ERK: extracellular signal-related kinase; Jab: Jun-activation domain binding protein; KynA: kynurenic acid; Kyn: kynurenine; LAT1: L-type amino acid transporter 1; L-Kyn: L-kynurenine; L-Trp: L-tryptophan; NOX: nicotinamide adenine dinucleotide phosphate oxidase; SARA: Smad anchor for receptor activation.