Experimental Study On Anti-inflammatory Treatment Of Psoriasis Targeting STAT3

Psoriasis is an immune-mediated polygenic inherited skin disease,and over activation of Signal Transducer and Activator of Transcription 3(STAT3)is one of the significant factors that induce psoriasis.Animal models,such as imiquimod(IMQ)and phorbol myristate acetate(PMA)-induced mice models,are important tools for researching the etiology,pathogenesis,and treatment of psoriasis,.Although the current treatment of psoriasis is effective,it can not achieve long-term remission.Therefore,it’s still an important task to continue to find novel,safe and effective anti-psoriasis drugs.Quercetin,a flavonoid widely found in fruits and vegetables,has many biological activities such as anti-oxidation and anti-inflammation.Shpingosine-1-phosphate(SIP)is a bioactive lysophospholipid metabolite that regulates responses and functions of a variety of cellular and organ systems.SIP may propagate its signals by activating its cell surface receptors(S1PR).There are three sections for this study.The aim of our first study is the construction and comparison of animal models of psoriasis.The IMQ and PMA-induced psoriatic mice models were established,and a new modeling method with the activation of Dendritic Cells(DC)after Keratin 17(K17)administration was explored.The results showed both IMQ and PMA led to psoriasis-like lesions,whereas the new modeling method only induced slight skin thickening,but the histology and appearance were not obvious,and further optimization was required.Our second study aims to investigate the theraputic function of quercetin.The results demonstrated that quercetin played an important role in regulating STAT3 signaling pathway to alleviate psoriatic skin lesions.In this section,HaCaT cells were stimulated with IL-6/IL-22,and the activation of STAT3 signaling pathway and the expression of psoriasis marker protein K17 were detected.The abnormal hyperplasia and differentiation phenotype of HaCaT cells were observed,to investigate the effect of quercetin treatment on this phenomenon.The results showed that in response to the Th17 related cytokines IL-6/IL-22 stimulis,the activation of STAT3 and the expression of K17 were inhibited by quercetin.In addition,in IMQ-induced psoriasis mice model,administration of quercetin could alleviate the pathological phenotype of the lesion.Our last study aims to investigate the impacts of S1P signaling on psoriatic skin lesions.The results showed that,through the analysis of clinical samples and experiments in vitro and in vivo,expression of S1PR3 increased significantly in psoriatic lesions.In human skin keratinocytes cultured in vitro,inflammatory factors IL-6/IL-22 could induce activation of the STAT3 pathway,meanwhile,the expression of S1PR3 was upregulated.After SiRNA interference technique,which was used to reduce the expression of S1PR3 gene in keratinocytes,blocking the expression of S1PR3 could significantly inhibit the activation of STAT3 pathway.In addition,FTY-720,a specific SIP receptor inhibitor,could inhibit STAT3 phosphorylation through downregulating S1PR3,the in vivo experiments also indicated that blocking the interaction of SIP and its receptors could also alleviate psoriatic skin lesions in imiquimod(IMQ)induced psoriasis mice model.