Role And Mechanism Of KLF2 In Psoriasis-Like Dermatitis Mice With Metabolic Syndrome

BackgroundPsoriasis is a common relapsing disease.The exact mechanisms of psoriasis are not yet fully elucidated.Studies have confirmed that psoriasis represents a chronic inflammation disease closely related to T cell immunity,the IL-23/T helper cell 17(Th17)axis plays an important role in psoriasis.Psoriasis has been associated with numerous comorbidities,including metabolic syndrome and cardiometabolic disease.Research have shown that metabolic syndrome and psoriasis share common pathogenic features,and the metabolic syndrome is an important cause of morbidity in patients with psoriasis.Current common drugs used in the treatment of psoriasis,such as methotrexate and cyclosporin,may adversely affect metabolic syndrome.Therefore,it is urgent to explore the underlying mechanism between psoriasis and metabolic syndrome to find suitable therapeutic targets.It has been reported that Krüppel-like factor 2(KLF2)might mediate atheroprotective effects by regulating lipid metabolism,and is participated in ameliorating inflammatory diseases like multiple sclerosis,rheumatoid arthritis,and coronary atherosclerosis.KLF2has been confirmed to play an anti-inflammatory role by regulating T cell immunity,and T cell-related immune signals are involved in the initiation and maintenance of psoriasis.Therefore,we hypothesized that KLF2 may be contribute to the inflammatory process of psoriasis.This study intends to construct a mice model of psoriasis,clarify the correlation between KLF2 expression and psoriasis inflammation.Atorvastatin was used to activate KLF2 expression in psoriasis mice,to study the effects of KLF2 on the infiltration of inflammatory cells and keratin proliferation in the skin.We construct a mice model of psoriasis-like dermatitis with metabolic syndrome,atorvastatin activated KLF2 expression on this model to investigate the influence of KLF2 on the comorbidity of psoriasis-like dermatitis and metabolic syndrome,and the interaction between KLF2 and NF-κB was also explored in both models.By exploring the role and clinical significance of KLF2 in psoriatic dermatitis mice with metabolic syndrome,this study may provide a new solution for the comorbidity of psoriasis and metabolic syndrome.ObjectiveActivating KLF2 expression by treating psoriatic mice with atorvastatin,and confirm the effects of KLF2 in psoriasis-like dermatitis.Then,we construct a mice model of psoriasis-like dermatitis with metabolic syndrome,and investigate the influence and therapeutic significance of KLF2 in the comorbidity of psoriasis and metabolic syndrome.Method1.The expression of KLF2 in the skin of patients with psoriasis.The expression of KLF2 in the skin tissues of patients with psoriasis vulgaris and healthy subjects was detected by Immunohistochemistry.2.KLF2 in mice skin have an effect on psoriasis-like inflammation and the mechanism research.C57BL/6 mice were randomized to normal diet control group,model group,atorvastatin group of low(5 mg/kg),medium(10 mg/kg)and high(20 mg/kg)dosage.A mouse model of psoriasis-like dermatitis was induced by 5%imiquimod cream.The level of KLF2 in mice skin was detected Immunohistochemical staining and Western Blot.The degree of skin inflammation on the back of mice was evaluated from erythema,scales,thickness scores,and HE staining;the number of Vγ4~+γδT cells and Vγ4~+IL17A~+T cells in the epidermis and dermis were detected by flow cytometry;and the levels of proinflammatory cytokines in the skin were detected by q PCR.Western Blot examine the level of NF-κB phosphorylated protein.3.Effect and mechanism of KLF2 in psoriasis-like dermatitis with metabolic syndrome.C57BL/6 mice were randomized to normal diet control group(ND),normal diet model group(ND-IMQ),high fat diet control group(HFD),high fat diet model group(HFD-IMQ),and high fat diet atorvastatin group(HFD-IMQ,20 mg/kg).Topical application of 5%imiquimod cream after high fat diet to develop a mice model of psoriasis-like dermatitis and metabolic syndrome comorbidity.The metabolic syndrome was evaluated by body weight,fatty liver and lipid levels.Immunohistochemistry and Western Blot were used to detect the level of KLF2 in the skin of mice.The degree of skin inflammation on the back of mice was evaluated from erythema,scales,thickness scores,and HE staining;the number of Vγ4~+γδT cells and Vγ4~+IL17A~+T cells in the epidermis and dermis were determined by flow cytometry;the expression of proinflammatory cytokines in the skin were detected by q PCR.Western Blot examine the level of NF-κB phosphorylated protein.Result1.The expression of KLF2 in the skin of psoriasis was decreased.2.The level of KLF2 in psoriatic mice was lower than that in the normal healthy mice.The expression of KLF2 in each dose of atorvastatin group was higher than that in the model group,and the higher the concentration of atorvastatin,the higher the level of KLF2.3.Compared with the psoriasis group,the psoriatic lesions in each dose group of Atorvastatin were significantly reduced;and the number of Vγ4~+γδT cells and Vγ4~+IL17A~+T cells in the epidermis and dermis were decreased,the expression of proinflammatory cytokines in the skin were downregulated,and the level of p-NF-κB protein was decreased in each dose group of Atorvastatin.4.Building successfully the model of the psoriasis-like dermatitis with metabolic syndrome in mice.Compared with the psoriasis mice,mice with psoriasis and metabolic syndrome comorbidity showed more severe skin inflammation while having metabolic disorders such as overweight,fatty liver and hyperlipidemia.And the expression of pro-inflammatory cytokines in the skin of mice with psoriasis and metabolic syndrome comorbidity were increased.5.Compared with the high fat diet control group,the level of KLF2 in psoriasis-like dermatitis mice with metabolic syndrome was decreased.Compared with the high fat diet psoriasis group,the level of KLF2 was increased in atorvastatin group,psoriasiform lesions in atorvastatin group mice were significantly relieved,the number of Vγ4~+γδT cells and Vγ4~+IL17A~+T cells in the epidermis and dermis were decreased,the expression of pro-inflammatory cytokine was downregulated,and the level of p-NF-κB protein was reduced.At the same time,the level of blood lipids in atorvastatin group mice were decreased.ConclusionIn conclusion,KLF2 deficiency in skin tissue may be a key link in promoting the deterioration of psoriasis inflammation;Atorvastatin was used to activate KLF2 expression in the skin,which may inhibit Vγ4~+IL17A~+T cell infiltration and pro-inflammatory cytokine secretion in the skin by regulating the NF-κB signaling pathway,and alleviate psoriasis-like dermatitis.In addition,atorvastatin was treated in psoriasis-like dermatitis mice with metabolic syndrome to improve skin inflammation and reduce blood lipid metabolism by activating KLF2 expression.