Anti-Psoriatic Effects and IL-22 Targeting Mechanism of Indirubin by Suppressing Keratinocyte Inflammation and Proliferation

Indigo naturalis, which is extracted from the leaves and branches of Baphicacanthus cusia (Nees) Bremek, has traditionally been used to treat psoriasis. The current study aimed to examine a new mechanism of the components of indigo naturalis, including indirubin, indigo, and tryptanthrin. The anti-psoriatic effects were assessed by the proliferation biomarkers (Ki67, K16), cell cycle progression, ROS production, and interleukin profiling (ICAM-1, TNF-alpha, IL-6, and IL-8) in IL-22-treated HaCaT cells. Among the components, indirubin significantly decreased intracellular ROS production and lowered the production of ICAM-1, TNF-alpha, and IL-6 in IL-22-treated HaCaT cells. Indirubin, indigo, and tryptanthrin could decrease the proportion of Ki67-positive cells, but only indirubin decreased the proportion of cells entering the S phase and suppressed the expression of cyclin D1 and cyclin E1 in IL-22-treated HaCaT cells. Indirubin significantly suppressed the phosphorylation of STAT3 and ERK. In vivo, IL-22 was intradermally injected into mouse ears for six days and topically treated with 0.1% or 1% indirubin. In the IL-22-injected mice, treatment with indirubin inhibited epidermal hyperplasia. Immunohistochemistry and western blot analysis demonstrated the downregulation of K16 expression in psoriatic lesions. These results suggest that indirubin, which is a major component of indigo naturalis, may have therapeutic potential in an IL-22-induced psoriasis model.