Activation of the aryl hydrocarbon receptor (AhR) through its natural ligands, has been found to reduce skin inflammation, reduce oxidative stress, and upregulate skin barrier protein expression. AhR also inhibits the generation, persistence, and cytokine production of resident memory T cells in the skin. Stem cell released molecules (secretome) from adipose mesenchymal stem cells includes kynurenine, which is an AhR agonist.

The molecules released (secretome) from adipose mesenchymal stem cells (ADSCs) are diverse (Maguire, 2013) and and have many immunotherapeutic actions. Recent studies provide evidence that one mechanism by which the secretome of ADSCs act is through their agonist activities at Aryl hydrocarbon receptors (AhR). Such AhR agonist activity is highly therapeutic to eczema (Eichenfield et al, 2023).

The aryl hydrocarbon receptor (AhR) is expressed in various tissues characterized by a rapid growth rate, including human skin. Kynurenic acid, a product of tryptophan metabolism enzymatically formed from kynurenine, is a natural ligand for AhR. However, AhR is a promiscuous receptor, binding many unnatural ligands such as environmental toxins. This is important, because if the AhR is activated by unnatural ligands, such as air pollution (PM2.5 for example), ill effects can result. The soluble factors (kynurenine and downstream metabolites) generated by IDO (Indoleamine 2,3-dioxygenase) can bind and activate the aryl hydrocarbon receptor to promote Treg cell differentiation and the induction of dendritic cells expressing an immunosuppressive phenotype. Further, in a dose-dependent response, kynurenine upregulates the expression of immunosuppressive genes, such as TGFB1 and IDO1.

Mechanistically, ADSCs release kynurenine, which is a tryptophan metabolite catalyzed by IDO, to activate the aryl hydrocarbon receptor and enhance its downstream target NFE2L2 in macrophages. NFE2L2-encoded NRF2 not only functions as a master regulator of antioxidant defense but also represses the expression of inflammatory genes. As expected, NRF2 upregulation in macrophages was inhibited by inhibiting IDO and 1-methyltryptophan (1-MT), and the anti-inflammatory effect of ADSCs on macrophages was blocked when NRF2 expression in macrophages was silenced. Kynurenic acid, another IDO-derived metabolite that shares the same aryl hydrocarbon receptor as kynurenine, can promote TNF-α-stimulated gene-6 (TSG-6) expression, which is also released from ADSCs, and alleviate neutrophil infiltration of tissues (Wang et al, 2018).

In summary, the secretome from ADSCs contains a number of molecules (IDO, kynurenine, kynurenic acid) that naturally activate aryl hydrocarbon receptors to reduce inflammation in the skin, and provide long term therapeutic benefit to skin diseases such as Eczema and Psoriasis.