Pathogenesis Of UV-induced Skin Damage In Systemic Lupus Erythematosus

Systemic lupus erythematosus(SLE)is an autoimmune inflammatory disease characterized by multiorgan and multisystem involvement,also accompanied with the production of autoantibodies.Skin injury is one of the most important features of systemic lupus erythematosus.There are many factors that cause skin lesions in SLE,and its pathogenesis remains unclear.It is known that ultraviolet(UV)radiation can induce and aggravate skin lesions in patients with SLE,but the mechanism of light sensitivity of skin in SLE is unknown.In this study,we have explored the mechanism that skin is sensitive to UVinduced injury in SLE.To study the UV-induced lupus-like skin lesions,we used lupus-prone mice(MRL/lpr mice),and model of skin inflammation induced by lupus serum.We used pathological staining and immunohistochemistry to evaluate the characteristics of skin lesions in mice.In vitro,agarose gel electrophoresis was used to verify that UV irradiation of cells caused its necrosis and release a large amount of DNA.Flow cytometry was used to detect the effect of DNA on Fc? receptor expression,Western blotting was used to examine the pathway activation,and the production of inflammatory cytokine triggered by DNA was detected by ELISA.We further investigated the cooperation between IgG and DNA by detect the activation of Syk and I?B? signaling.In vivo,we have obtained the following results: 1.t UV irradiation accelerated and aggravated skin damage in MRL/lpr mice;2.a large amount of IgG deposition in skin after UV irradiation in MRL/lpr mice;3.IgG in serum of SLE patients was the leading cause of skin lesions after UV irradiation,and not the IgG from normal human serum,but only the IgG of SLE patients can trigger significant inflammation in skin;4.Monocytes-macrophages were the major infiltrating cells during UV-induced skin lesions,but not T cells or B cells,meanwhile,the TNF-? mainly produced by monocytes was also significantly increased;5.UV irradiation did not induce obvious skin damage in TNF-? deficient mice and C57BL/6 mice with monocytes depletion,In vitro,we have obtained the following results: 1.DNA from what increased the expression of Fc? receptor(Fc R)in monocyte-macrophages,whereas IgG reduced Fc?receptor expression by binding to Fc? receptor;2.Deposited lupus IgG could cooperate with DNA to promote phosphorylation of Syk signaling;3.Double-stranded DNA(What)obviously activated I?B? phosphorylation,and IgG could further enhance this phosphorylation;4.R406,a Syk inhibitor,suppressed the phosphorylation of Syk,but not I?B?,while chloroquine(inhibitor of Toll-like receptor)could inhibit I?B?activation but not that of Syk.Thus,there is no obvious correlation between Syk and I?B? phosphorylation;5.ELISA results showed that TNF-? was produced by DNAtriggered monocyte-macrophage,but the existence of IgG enhanced the inflammatory cytokines production.Based on the above results,we concluded that: necrotic keratinocyte producing large amounts of DNA and IgG deposited in skin are two major features of UV-induced skin lesions in SLE;Monocytes play a vital role in the pathogenesis of lupus skin disease;DNA can upregulate the expression of Fc? receptor on the surface of monocytes,which allows Fc? receptor binding more IgG to enhance IgG/Fc R signaling pathway,and promote inflammatory progression.IgG also binds DNA to form immune complexes to activate inflammatory cells and upregulate the production of TNF-?.Our research also reveals that lupus IgG deposition and Fc? receptor expression play important role in pathogenesis of UV-induced skin injury of SLE,while IgG/Fc R can be used as a therapeutic target for UV-induced skin lesions of SLE.