Interleukin-18 Affects Skin Inflammation In A Mouse Model Of Imiquimod-induced Psoriasis

Background: Psoriasis is one of the most common chronic inflammatory skin diseases characterized by abnormal proliferation and unusual differentiation of keratinocytes.It appears circumscribed,erythematous papules and plaques with silvery thick scales.At present,there are about 200 million psoriatic around the world.Psoriasis,as a reoccurring and relapsing human skin diseases,leads severely reduce the quality of life in patients.Though clinically well characterized,as an immune disordered and gene burden complex disease,the exact etiology and pathogenic mechanisms are still unknow in detail.Interleukin(IL)18,as a member of the IL-1 family of cytokines,is a pleiotropic immune regulator.IL-18 induces immune cells to secrete interferon(IFN)? and plays an important role in inflammatory and autoimmune skin diseases.Psoriasis is associated with T helper(Th)1,Th2 and Th17 cells responses.Under Th1 cells existing condition,IL-18 might recruit dendritic cells expressing IL-18 receptor(IL-18R)into infectious areas in psoriasis.IL-18 from keratinocytes in synergy with IL-12,inducing Th1 cells secret IFN?,play a proinflammatory role in psoriatic lesions.In addition,IL-18 could also stimulate ??T cells and Th17 cells producing IL-17,which is a primary cytokine related to the pathogenesis of psoriasis.Previous studies showed that IL-18 expression is increased in active and progressive psoriatic lesions compared to stable lesions.Moreover,serum levels of IL-18 positively are correlate with the psoriasis area and severity index(PASI).Although IL-18 showed a positive relation with psoriasis-like skin inflammation,no study to date characterized how IL-18 affects psoriasis.In addition,recent studies revealed that IL-18 plays a protective role in some diseases and immunological conditions.Therefore,we investigate the effects of IL-18 on psoriasis by establishing psoriasis model of mouse.To explore the correlation between IL-18 and psoriasis,and then look for possible reasons and pathogenesis of human psoriasis.Materials and Methods: Experiment subjects: 16 weeks old female C57BL/6 and IL-18 Knockout(C57BL/6 background)mice were randomly divided into four groups: 1)wild-type(WT)control,2)IL-18 KO control,3)WT + imiquimod(IMQ)and 4)IL-18 KO + IMQ.All mice were shaved on their dorsal surface to expose a 2×3cm area.The IMQ-induced mice received a daily application of IMQ using a dose of 62.5mg IMQ cream(5%)while control mice received an identical volume of Vaseline cream.Hematoxylin and eosin staining(HE)staining:HE staining was performed using standard procedures.The sections of IMQ-induced mice were used to compare the differences of histopathology between IL-18 KO mice and WT mice in psoriasis-like skin inflammation.Realtime polymerase chain reaction(Realtime-PCR): The skin lesions of IMQ-induced mice were used to detect the m RNA levels of inflammatory related cytokines,including IL-17,IL-23,IL-22,IFN-?,IL-12,IL-1?,IL-4,IL-15,IL-18 R and IL-27.The m RNA levels of above cytokines were compared in IL-18 KO mice and WT mice.Immunohistochemistry staining: In IMQ-induced mice,the expression level of IL-1?,IL-27,Chemokine(C-X-C motif)ligand 1(CXCL1)and Ly6 g were detected in skin biopsies,and then we compare the difference of expression between two groups.Results: 1.Gross morphology of mice skin lesions and PASI score: In mice model of psoriasis,the skin biopsies of WT mice showed evidence of erythema and epidermal thickness with silvery thick scales,whereas no obvious skin lesions were present in IL-18 KO mouse.Cumulative PASI scores showed that IL-18 KO mice had significantly lower scores than WT mice on days 3 to 7 in response to IMQ(P<0.001,Independent-sample t test).2.Histopathological manifestation: Skin specimens of mice treated with IMQ showed acanthosis and moderate cellular infiltration in the dermis.IL-18 KO mice showed a milder degree of acanthosis(Independent-sample t test,P<0.01)and cellular infiltration(Independent-sample t test,P<0.01)as compared with WT mice.3.Realtime PCR: In mice model of psoriasis,the results of Realtime-PCR showed that the expression of IL-1?(Kruskal–Wallis test,P<0.05),IL-27(Kruskal–Wallis test,P<0.01)and IL-4(Kruskal–Wallis test,P<0.01)were all significantly increased in IL-18 KO as compared to WT mouse in m RNA levels.IL-17 was decreased in IL-18 KO versus with WT mice(Independent-sample t test,P<0.05).The m RNA expression of IFN-?,IL-23,IL-22,IL-12,IL-15 and IL-18 R were not showed any difference between IL-18 KO mice and WT mouse.4.Immunohistochemical staining: In mice model of psoriasis,the expression level of IL-1? and IL-27 were significantly increased in IL-18 KO mice as comparing with WT mice.Accordingly,these results were consistent with those of the m RNA.IL-18 KO mice versus with WT mice,the expression of Ly6 g was increased(Kruskal–Wallis test,P<0.01).However,CXCL1 decreased in IL-18 KO mice when compared to WT mice(Independent-sample t test,P<0.01).Conclusions: In mice model of psoriasis,IL-18 exacerbates inflammation of skin lesions and effects on PASI scores.IL-18 influences the formation of scales and Munro's microabscesses in IMQ-induced psoriasis-like skin inflammation.IL-18 regulates the expressions of IL-1?,IL-17,IL-4 and IL-27 in m RNA levels.IL-18 influences the expressions of chemokine CXCL1 and Ly6g(a surficial hallmark of neutrophils)and may be involved in inflammatory forms of neutrophils.