Cis-khellactone inhibited the proinflammatory macrophages via promoting autophagy to ameliorate imiquimod-induced psoriasis

Abstract Psoriasis is a chronic inflammatory skin disease with unresolved pathogenesis. Studies on the pathogenesis of psoriasis have been extensively carried out, but treatments are still not satisfactory. In this study, we found improvement after treatment with cis-khellactone, a small molecular natural product, in imiquimod (IMQ)-challenged C57BL/6 mice. Cis-khellactone clearly reduced the level of cytokines in psoriatic skin, including IL-23, TNF-α, IL-1β and IL-6, while limiting inhibition of IL-17A, which is produced by Th17 cells. Cis-khellactone treatment specifically decreased dermal macrophage infiltration in psoriatic skin but not neutrophils or T cells. Additionally, compared to the control group, cis-khellactone significantly decreased the activation of NF-κB p65 in these infiltrated macrophages. Further study revealed that cis-khellactone suppressed pro-inflammatory phenotypic macrophages by promoting autophagy. Blocking autophagy by silencing Beclin1 or autophagy-related gene (Atg) 7 abrogated the effect of cis-khellactone on macrophages. The autophagy-dependent improvement in psoriasis from cis-khellactone treatment was further manifested by its limited effects on skin lesions in chloroquine (CQ)-treated mice. Moreover, cis-khellactone showed lower toxicity than MTX in macrophages and primary hepatocytes. Taken together, cis-khellactone selectively modulated macrophage function and phenotype by inducing autophagy to ameliorate psoriasis in IMQ-induced mice. Our research provides an effective strategy for the treatment of psoriasis.