Role Of P38α Signaling In Keratinocytes In Psoriasiform Skin Inflammation

Objective:Studies have been shown that the expression and activity of p38 in keratinocytes（KC）of patients sufferred from psoriasis are significantly increased,indicaing that p38αmitogen-activated protein kinase（MAPK）might play a role in the pathogenesis of psoriasis,but the potential mechanism is still not well known.In this dissertation,we used a psoriasis disease model,imiquimod（IMQ）-induced mouse psoriasis-like skin inflammation,to dissect the role of p38αsignaling in KCs in psoriasis pathogenesis.Methods:（1）For In Vivo experiments,IMQ was topically applied to wild-type（WT）mice and mice with p38αspecifically deletion in KC(Here refer as p38α^ΔKC)to induce psoriatic-like inflammation.The disease severity was recorded every day.Skin inflammation was examined by histopathological assay.The expression of inflammatory cytokines,chemokines and antimicrobial peptides in KCs or skin tissue was measured by quantitative real-time quantitative PCR（qPCR）.Flow cytometry was used to check inflammatory cell infiltration in the skin,proliferation and apoptosis of KC,dendritic epidermal T cells（DETCs）andgdT cells,as well as the activation of dendritic cells（DCs）in the skin.（2）For In vitro experiments,skin cells from WT and p38α^ΔKC neonatal（born 1 to 3 days）were cultured for KCs.KCs were stimulated with R848,IL-1b,IL-17A,TNF-a,respectively,and qPCR was used to measure the expression of inflammatory factors,chemokines and antimicrobial peptides.Results:（1）In IMQ-induced psoriasis-like skin inflammation model,mice with p38αspecifically deletion in KCs had less disease severity and inflammatory cell infiltration in the skin than WT mice.The expression of certain psoriasis-related genes in skin tissue and KCs of p38α^ΔKC mcie were also significantly descreased.The KCs from p38α^ΔKC mcie had less proliferation upon IMQ treatement than those from WT mice.However,the differentiation of T cells,the activation of DCs,and the proliferation and apoptosis of DETC and T cells in the skin were comparable between WT and p38α^ΔKC mcie.（2）In vitro experiments showed that deletion of p38αin KCs had significant effect on responses to R848,IL-17A,IL-1b,and TNF-astimulation.Conclusion:p38α signaling in KCs promotes psoriasis development might be through enhancing KC proliferation and inflammatory immune response to certain psoriasis triggers.