Blood Coagulation Factor ? Contributes To The Development Of Psoriasis

Psoriasis is a chronic,immune-mediated inflammatory disease that primarily affects the normal physiological function of the skin and has a complex genetic structure,the global prevalence of psoriasis was about 2-3%.Plaque-type psoriasis is the most pervading type of psoriasis in patients,accounting for about 90%of all psoriatic patients.Psoriasis is mainly mediated by dendritic cells and T cells and jointly involved by antigen presenting cells,neutrophils and keratinogenic cells,the IL-23/T_H17 axis plays a vital role during the development of psoriasis.Although the current scientific research has analyzed and clarified the pathogenesis of psoriasis to a large extent,there are still many unclear questions about the pathological mechanism of psoriasis to be further explored.Factor XII(FXII)is a coagulation factor in the intrinsic coagulation pathway,which mainly produced by the liver and secreted into the blood circulation system.Although the enzymatic activity of the FXII has been thoroughly studied,and the catalytic functional domain of the FXIIa has been resolved,functions of the enzymogen FXII have been rarely identified.Recent advances suggestted that FXII's functional activity in vivo is far beyond its own basic properties as a coagulation factor.FXII is involved in complex receptor interactions,synergistically affect the behavior of immune cells,and promotes pathologic and physiological response processes.The specific mechanisms for FXII playing functional activity in the zymogen forms have not been fully clarified,and more research on FXII and autoimmune or inflammatory diseases is needed.Studies have reported that psoriatic plasma has a tendency to produce high coagulation status,associated with complications including cardiovascular disease and metabolic syndrome.In this study,its coagulation status was detected,and the results showed that APTT clotting time was significantly below normal value,it indicated some changes were in the plasma of intrinsic coagulation pathway in psoriatic patients.Further detection of intrinsic coagulation factors of plasma showed that FXII expression level was significantly higher in psoriatic patients than in normal controls,while that for Factor XI,Factor X,thrombin and fibrinogen has no significantly change.Meanwhile,the expression level of FXII at the skin lesions in psoriatic patients and two psoriatic mouse models were also significantly increased.The overexpressed FXII was mainly distributed in the stratum corneum of the epidermis and the highest expression of FXII was observed at the junction of the epidermis and dermis.Excessive expression of FXII at skin lesion tissue in psoriatic patients may be associated with hyperproliferation of keratinocytes.The results of two different cell proliferation experiments showed that in the presence of Zn²⁺,FXII significantly promoted the proliferation of human keratinocytes,and showed a significant quantitative-effect relationship.Further detecting its downstream signaling pathway,both MAPK-ERK1/2 and NF-?B-P65 signaling pathways were involved in the FXII-mediated kerocytes proliferation process through receptor u PAR,however,activation of the signaling pathway PI3K-AKT was not detected during this proliferation process.FXII is a key component of the Kallikrein-kinin system(KKS)that regulates inflammatory responses by releasing the terminal product BK.In psoriatic patients and two different psoriatic mice,the expression level of BK was significantly increased in plasma;the expression level of BKB₂R in skin lesion was also upregulated than normal control;and the expression level of psoriatic landmark inflammatory factors such as TNF-?,IL-17 and IL-23 in plasma was also significantly elevated.Excessive expression of FXII led to upregulation of BK expression levels,which in turn induced increases of BKB₂R expression levels,and ultimately increased the production of downstream inflammatory reactions.The FXII expression level of plasma and skin lesions in psoriatic patients and mice was significantly increased,which could promote keratinocyte proliferation and inflammation.Thus,FXII^-/-mice and FXII inhibitor were used to reverse verify the role of FXII in the development of psoriasis.In IMQ-induced psoriatic mouse model,Improvement of typical symptoms of skin lesions and a significant reduction in the concentration of inflammatory factors in the skin lesions were detected in FXII^-/-mice;the distribution ratio of DCs and T_H17 cells in the lymph nodes and spleen in FXII^-/-mice were significantly below normal value.Through intravenous administration of Infestin-4(a FXII inhibitor)into two psoriatic mice,Infestin-4 could also significantly improve the symptoms.In this study,we found FXII is highly expressed in the skin lesions and plasma of both psoriatic patients and psoriatic mouse models,and revealed the important promoting role of FXII in the pathological mechanism of psoriasis from three different aspects.In psoriatic skin lesions,overexpressed FXII could significantly promote keratinocytes proliferation.Overexpressed FXII promoted BK production through KKS pathway and aggravated downstream inflammatory response in psoriatic blood.In psoriatic immune organs,FXII could regulate DCs distribution ratio and T cell polarization and then promoted psoriasis progress.There were significant treatment effects on psoriatic mice after gene knockout of FXII or inhibitor administration,and FXII may be an important target for psoriasis treatment in the future.