The Role Of Long Noncoding RNA In Regulation Of Interferon In Systemic Lupus Erythematosus

Background: Systemic lupus erythematosus(SLE)has become a medical problem that has not yet been overcome because of its complex immune phenotypes and highly heterogeneous clinical manifestations.Large-scale gene transcriptome analysis studies have shown that the two most important features of systemic lupus erythematosus are interferon signature and neutrophil-related signature.However,whether there is a certain internal relationship between these two signatures is still unknown.Neutrophils are the most abundant class of cells in blood,and their roles of sources of high level of interferon in lupus are gaining increasing attention.The interferon signature of systemic lupus erythematosus refers to the high expression of a series of interferon stimulated genes,but even if the overall function of these encodable genes still can not cover all the manifestations of lupus,it is likely that interferon stimulated long noncoding RNAs could also play a very important role in the disease.There is still a lack of screening and functional study of these long noncoding RNAs,relevant research should be conducted.Objectives: Screening long noncoding RNAs that can be regulated by interferon and simultaneously have an abnormal expression in systemic lupus erythematosus.Dissect the role of the long noncoding RNA in regulation of neutrophils interferon production and analyze their association with lupus disease.Methods: Compare the interferon production capacity of neutrophils from systemic lupus erythematosus patients and healthy controls by TLR7/8agonist R848 stimulation.RNA seq was used to screen the long noncoding RNAs which were expressed abnormally in lupus and were strongly induced by interferon.The expression of the long noncoding RNA was knocked down by electroporation of antisense oligos(ASO)into primary neutrophils.Interferon production was measured in m RNA level by q PCR and protein level by ISRE reporter gene assay after R848 stimulation.Blood samples of lupus patients were collected to analysis the correlation between the long noncoding RNA and the disease clinical manifestations.Results: Neutrophils from lupus patients produced more interferon by R848 stimulation than that from healthy controls,and the capacity of neutrophils to produce interferon by R848 stimulation enhanced after interferon prime.Lnc RNA-CMPK2 is an important interferon stimulated long noncoding RNA,which is highly expressed in lupus,and the expression level is related to lupus interferon score and disease activity.Knockdown of lnc RNA-CMPK2 can reduce neutrophils interferon production by R848 stimulation.The mechanism may rely on reducing the expression of IRAK4 and IRF7.Conclusions: Lnc RNA-CMPK2 is an important long noncoding RNA in the pathogenesis of systemic lupus erythematosus,its role is to promote the production of interferon by neutrophils,and to reduce the expression of lnc RNA-CMPK2 might provide a new idea for the treatment of systemic lupus erythematosus.