Dihydroartemisinin Alleviates Psoriasis-like Skin Inflammation In Mice By Inhibiting The Proliferation Of Keratinocytes And Expression Of Pro-inflammatory Cytokines

Background:Psoriasis is one of the four intractable diseases in dermatology.There is no effective treatment for psoiasis.The proliferation and activation of keratinocytes is not only the main pathological feature of the disease,but also the key to the vicious circle of inflammation in psoriasis.So Keratinocytes play an important role in the development of psoriasis.Recent studies have found that Dihydroartemsinin has obvious anti-Inflammatory effects in a variety of autoimmune diseases.The preliminary data of our research group showed that Dihydroartemisinin could be exceeding inhibited the proliferation of HaCaT cells and the production of proinflammatory cytokines such as IL-17A and IL-23 secreted by HaCaT cells,suggesting that dihydroartemisinin may Inhibit proliferation of keratinocytes and the production of pro-inflammatory cytokines secreted by keratinocytes to improve psoriasis.Objectives:To clarify the inhibition of Dihydroartemisinin on the psoriasis-like skin inflammation in mice,and explore the mechanism of Dihydroartemisinin inhibiting the proliferation of keratinocytesMethods:BALB/c mice ware randomly divided into 4 groups-control group,model group,Dihydroartemsinin low group and Dihydroartemisinin high group.Psoriasis-like skin inflammation was induced by topically applying 5%imiquimod cream on the back skin once a day for 6 consecutive days.The mice were treated with Dihydroartemisinin by intragastric administration at doses of 25mg/kg/d and 50mg/kg/d 1h before imiquimod treatment.The model group and the control group were given an equal volume of 0.5%sodium caiboxymethyl cellulose by intragastric administration.During the modeling period,back skin of mice was observed and the PASI clinical scores were evaluated daily.H&E staining was used to observe the histological changes in back skin of mice among the four groups.Immunohistochemcal staining was used to detect the expression of Ki67 in mice skin.The levels of IL-1β,IL-18,IL-6 and CXCL-lin the skin tissue were determined by ELISA.The expression of NF-κB and MAPK signaling pathways related proteins were detected by western blot.Results:The experimental results of mouse psoriasis model showed that dihydroartemisinin could relieve the skin injury caused by imiquimod,and significantly alleviate the symptoms of erythema,scaly,and skin thickening.The PASI clinical score showed that compared with the model group,the erythema,psoriasis skin thickness and total score of the mice in the administration group were significantly reduced(P<0.05).H&E staining showed that the number of infiltrating inflammatory cells in the dermis was reduced,the thickness of the epidermis was thinned the hyperkeratosis was reduced,and the process of the spinous layer was shortened significantly.Moreover,Dihydroartemisinin could significantly reduce the number of Ki67 positive cells in epidermis by immunohistochanical staining.In addition,expression of IL-1β,IL-18,IL-6 and CXCL-1 were decreased in the skin tissues on day 3 and day 6 in the Dihydroartemisinin groups(P<0.05).Compared with the model group,Dihydroartemisinin groups significantly inhibited the expression of NF-κB(p65),which in nuclear,p-p38 and p-ERK in psoriatic skin lesions with a does-dependent manner(P<0.05).Conclusion:Dihydroartisinin can obviously alleviate imiquimod-induced psoriasis-like skin infammation in mice.The possible mechanism might be that Dihydroartemisinin inhibited the proliferation ofkeratinocytes and the production of proinflammatory cytokines secreted by keratinocytes via the MAPK and NF-κB signaling pathways.