PD-L1 Enhanced by cis-Urocanic Acid on Langerhans Cells Inhibits Vy4D y8T17 Cells in Skin Inflammation

Psoriasis is an IL-23/IL-17-mediated inflammatory autoimmune dermatosis, and UVB may contribute to immu-nosuppression and ameliorate associated symptoms. One of the pathophysiology underlying UVB therapy is the production of cis-urocanic acid (cis-UCA) by keratinocytes. However, the detailed mechanism is yet to be fully understood. In this study, we found FLG expression and serum cis-UCA levels were significantly lower in patients with psoriasis than in healthy controls. We also noted that cis-UCA application inhibited psoriasiform inflammation through the reduction of Vg4+ gdT17 cells in murine skin and draining lymph nodes. Meanwhile, CCR6 was downregulated on gdT17 cells, which would suppress the inflammatory reaction at a distal skin site. We revealed that the 5-hydroxytryptamine receptor 2A, the known cis-UCA receptor, was highly expressed on Langerhans cells in the skin. cis-UCA also inhibited IL-23 expression and induced PD-L1 on Langerhans cells, leading to the attenuated proliferation and migration of gdT-cells. Compared to the isotype control, a-PD-L1 treatment in vivo could reverse the antipsoriatic effects of cis-UCA. PD-L1 expression on Langerhans cells was sustained through the cis-UCA-induced mitogen-activated protein kinase/extracellular signal -regulated kinase pathway. These findings uncover the cis-UCA-induced PD-L1-mediated immunosuppression on Langerhans cells, which facilitates the resolution of inflammatory dermatoses.

Automated summary

Psoriasis is an inflammatory autoimmune dermatosis mediated by IL-23/IL-17, and UVB may suppress immunity and improve symptoms. One mechanism of UVB therapy involves the production of cis-urocanic acid (cis-UCA) by keratinocytes. This study found that FLG expression and serum cis-UCA levels were lower in psoriasis patients compared to healthy controls. It was also observed that cis-UCA inhibited psoriasiform inflammation by reducing Vg4+ gdT17 cells in mouse skin and lymph nodes. Additionally, cis-UCA induced PD-L1 expression on Langerhans cells, leading to suppressed proliferation and migration of gdT-cells.