Natural Compounds Tapinarof and Galactomyces Ferment Filtrate Downregulate IL-33 Expression via the AHR/IL-37 Axis in Human Keratinocytes

Abstract

Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and Galactomyces ferment filtrate (GFF), which are potent AHR modulators. We found that tapinarof and GFF upregulated IL-37 in NHEKs, which was canceled by the knockdown of AHR using siRNA transfection, indicating that AHR mediates IL-37 expression in NHEKs. Furthermore, we found that the knockdown of IL-37 resulted in the upregulation of IL-33, an alarmin cytokine with crucial roles in the pathogenesis of AD and psoriasis. These findings suggest that IL-37 negatively regulates IL-33 expression in NHEKs. Finally, we examined whether tapinarof and GFF treatment modulates IL-33 expression in NHEKs. Such treatment inhibited IL-33 expression, which was partially reversed by the knockdown of either AHR or IL-37. Taken together, our findings provide the first evidence that tapinarof and GFF could have potential to prevent IL-33-overexpressing disorders such as AD and psoriasis via the AHR/IL-37 axis.

Natural Product-Derived Compounds Targeting Keratinocytes and Molecular Pathways in Psoriasis Therapeutics

“…This is a potential therapeutic approach for psoriasis. [ 78 , 79 ]. In May 2022, tapinarof was approved by the FDA for psoriasis treatment as a topical cream following successful clinical trials that confirmed its effectiveness [ 94 , 95 ].…”

Galactomyces Ferment Filtrate Potentiates an Anti-Inflammaging System in Keratinocytes

“…Notably, GFF upregulated IL-37 expression in human keratinocytes in an AHR-dependent fashion [ 116 ] ( Figure 2 ). The GFF-induced IL-37 is biologically active, because it downregulates the expression of IL-33 in keratinocytes [ 116 ].…”

“…Notably, GFF upregulated IL-37 expression in human keratinocytes in an AHR-dependent fashion [ 116 ] ( Figure 2 ). The GFF-induced IL-37 is biologically active, because it downregulates the expression of IL-33 in keratinocytes [ 116 ]. Moreover, the GFF-AHR-IL-37-induced downregulation of IL-33 is canceled by the knockdown of either AHR or IL-37 [ 116 ].…”

“…The GFF-induced IL-37 is biologically active, because it downregulates the expression of IL-33 in keratinocytes [ 116 ]. Moreover, the GFF-AHR-IL-37-induced downregulation of IL-33 is canceled by the knockdown of either AHR or IL-37 [ 116 ]. Like GFF, the therapeutic AHR agonist tapinarof decreases IL-33 production in keratinocytes through the AHR-IL-37 axis [ 116 ].…”

“…Moreover, the GFF-AHR-IL-37-induced downregulation of IL-33 is canceled by the knockdown of either AHR or IL-37 [ 116 ]. Like GFF, the therapeutic AHR agonist tapinarof decreases IL-33 production in keratinocytes through the AHR-IL-37 axis [ 116 ]. These results agree with our previous finding that the IL-33 expression is downregulated through activation of the AHR-OVOL1 axis [ 117 ] and further point to a critical role of AHR in inducing IL-37 expression in human keratinocytes.…”