STING inhibition by H-151 is associated with amelioration of psoriasis severity via modulation of pathogenic T helper...

Psoriasis is a chronic immune-mediated skin disorder characterized by dysregulated activation of T helper (Th) cells. While Th1 and Th17 subsets are well-established contributors to disease pathology, the role of Th9 cells remains poorly understood. To investigate the relationship between disease severity and Th cell dynamics, we established a time-course imiquimod (IMQ)-induced psoriasis mouse model. Prolonged IMQ application resulted in progressive worsening of psoriatic inflammation, accompanied by increased populations of Th1, Th17, and Th9 cells, along with elevated levels of their associated cytokines. These findings indicate a strong correlation between the accumulation of pathogenic Th subsets and the severity of psoriatic inflammation. Stimulator of interferon genes (STING) signaling has been implicated in psoriasis pathogenesis, and the STING inhibitor H-151 has shown therapeutic potential by reducing inflammation in previous studies. However, its effect on the regulation of pathogenic Th subsets has not been elucidated. In this study, topical administration of H-151 significantly ameliorated disease phenotypes and reduced the populations of IFN-γ⁺, IL-17A⁺, and IL-9⁺ CD4⁺ T cells in lymph nodes, as well as their cytokine levels in CD4⁺ T cell supernatants and lesional tissues. Our findings provide the first evidence that H-151 exerts its therapeutic effects in psoriasis through coordinated suppression of multiple pathogenic Th subsets, including Th9 cells, thereby offering novel insight into the immunomodulatory mechanism of STING inhibition in psoriatic inflammation.