The Function And Mechanism Of E3 Ligase FBXW7 In Psoriasis

Psoriasis is a chronic skin inflammation disease caused by trauma,infection or bacteria.As a result of excessive secretion of several pro-inflammatory cytokines,keratinocytes from the skin epidermis expand rapidly and the oveiproliferation results in the formation of slivery scales.About 3%of the population worldwide suffer from the disease.Up to now,it is well accepted that interleukin 23 from innate cells like dendritic cells and macrophages drives the expansion of gamma delta T cells and its production of interleukin 17 is one of the main mechanisms during psoriasis progress.But how the key cytokine interleukin 23 is regulated is barely known.Plenty of work show that E3 ligase FBXW7 has great contribution to tumorigenesis and previous work shows that FBXW7 stabilizes RIG-I by Ub-mediated degradation of SHP2,thus,protects individuals from virus infection.But how FBXW7 participated in inflammation remains ambiguous.We found that FBXW7 is upregulated in psoriasis patients' lesional skin and imiquimod induced murine psoriasis model.Given that interleukin 23,the driven factor of psoriasis genesis,is mainly secreted by dendritic cells and macrophages,we generated transgenic mice in which FBXW7 is knocked out specifically in myeloid cells.Shaven back skin and ears were applied with imiquimod cream(5%)daily to imitate the psoriasis condition.We found that deficiency of FBXW7 in myeloid cells protected mice from psoriasis with the reduction of the number of gamma delta T cells accumulated in the dermis and the deduction of IL-17 secreted by gamma delta T cells.In vivo and in vitro experiments showed that deficiency of FBXW7 in DCs and macrophages results in the reduced production of IL-23.And Lysm+ FBXW7f/f bone marrow derived macrophages(BMDM)exhibited a more pronounced H3K9 trimethylation in the promotor region of IL-23.Also,we found that expression of H3K9me3 specific methyltransferase SUV39H2 is increased in Lysm+FBXW7f/f BMDM.Co-IP and immunofluorescence suggested that FBXW7 binds to SUV39H2.Furthermore,Lysm+FBXW7f/f BMDM showed less Ub-mediated degradation of SUV39H2.Therefore,our study indicates that FBXW7 binds to H3K9me3 specific methyltransferase SUV39H2 and mediates its degradation and leads to the reduction of H3K9me3 in IL-23 promotor region,and finally,promotes the production of IL-23.To conclude,FBXW7 regulates the production of cytokines from DCs and macrophages,and plays a pivotal role in the progress of psoriasis.Our study explores the function of E3 ligase FBXW7 in innate immune system and provide a possible way to develop drugs targeting IL-23 for psoriasis.