MSCs Alleviate The Lesions Of Psoriasis Like Dermatitis Mice By Inhibiting TYK2 Phosphorylation

Background and Objectives:Psoriasis is an inflammatory skin disease mediated by immune cells and immune factors,"which is characterized by abnormal epidermal hyperplasia and inflammatory cell infiltration.The infiltration of neutrophils,macrophages and dendritic cells in psoriatic lesions increases,and then activates natural killer cells and T cells to maintain the pathological cycle mediated by unique Th17 cells.Among them,IL-23/Th17 axis is considered to play a key role in psoriasis.The activation of T cells and its upregulation of inflammatory factors are considered to mainly affect the occurrence and development of psoriasis and promote the excessive proliferation and terminal differentiation of keratinocytes.Mesenchymal stem cells(MSCs)are adult pluripotent progenitor cells with low immunogenicity,strong self-renewal ability and strong immunomodulatory characteristics.They can regulate B cell proliferation and plasma cell differentiation,regulate macrophage polarization,inhibit DC maturation,inhibit neutrophil mobilization,inhibit NK cell and T lymphocyte proliferation through direct contact and release of soluble substances.It is considered to be a treatment for many autoimmune or inflammatory diseases,such as rheumatoid arthritis,systemic lupus erythematosus,Crohn’s disease,psoriasis and so on.It was reported that 2 patients with psoriasis vulgaris had obvious curative effect after MSCs transplantation,and no recurrence was observed for 4-5 years.However,the specific therapeutic mechanism of MSCs on psoriasis is not completely clear.The Janus Kinase Signal Transducer and Activator of Tran-scription(JAK-STAT)signalling pathway is an important cytokine signal transduction pathway.It plays a very important role in mediating cell proliferation,differentiation,apoptosis,immune regulation and stem cell development,and is closely related to autoimmune diseases.TYK2 is one of JAK proteins in JAK-STAT family.Its activation is involved in the activation,stability and proliferation of Th17.At present,relevant clinical studies have shown that small molecule TYK2 inhibitors also have a good effect on moderate and severe psoriasis.Considering that MSCs can inhibit the differentiation of CD4+T cells into Th17 cells,and the activation and proliferation of Th17 cells involved in the activation of TYK2 play a key role in the immune process of psoriasis,we speculate that MSC may reduce the severity of psoriasis by inhibiting TYK2 phosphorylation.This research will explore the possible therapeutic mechanism of MSCs on psoriasis like dermatitis mice through the following experimental design.Methods:1.BALB/C female mice aged 6-8 weeks were randomly divided into blank group,imiquimod group(IMQ group)and MSCs treatment group(IMQ+MSC group).The mouse model of psoriasis like dermatitis was established with imiquimod cream.During the modeling period,the skin lesions of the mice were photographed every day and the PSAI score was evaluated.The severity of skin lesions and the improvement of spleen size before and after MSc treatment were compared.2.The diseased skin tissues of mice in each group were stained with he and tissueimmunofluorescence.The thickness of skin lesions and the infiltration of CD4+T cells and CD11c+dendritic cells were compared.3.Protein was extracted from the diseased skin tissue of mice in each group.The relative expression levels of total TYK2 and p-TYK2 were detected by Western blot,and the relative expression levels of total TYK2 and p-TYK2 were compared;The pathological skin tissues of mice in each group were stained with tissue immunofluorescence,and the skin lesion ror of mice in each group was compared the degree of RORyT+Th17 cell infiltration.Results:1.The degree of erythema and scale in IMQ group was significantly worse than that in blank group,the size of spleen was significantly increased,and the PASI score gradually increased with the modeling time;After treated with MSCs,the severity of erythema and scales,spleen and PASI score of IMQ+MSCs group mice decreased compared with IMQ group mice.2.Compared with the blank group,the epidermal thickness of IMQ group was significantly thicker,and the infiltration of CD4+T cells and CD11c+dendritic cells was significantly increased;The epidermal thickness of IMQ+MSCs group was significantly lower than that of IMQ group,and the infiltration of CD4+ T cells and CD11c+dendritic cells was significantly reduced.3.The results of Western blot showed that there was no significant difference in the level of total TYK2 in each group,but the phosphorylation level of TYK2 in IMQ group was higher than that in blank group,and the phosphorylation level of TYK2 in IMQ+MSCs group was lower;The RORyT+Th17 cell infiltration of IMQ group increased and in IMQ+MSCs group RORyT+Th17 cell infiltration decreased.Conclusions:MSCs can alleviate the lesions of psoriasis like dermatitis mice by inhibiting TYK2 phosphorylation.