Background/Purpose: Interferon plays prominent role in systemic lupus erythematosus (SLE) pathogenesis while the source of high interferon in SLE is still confused, several cell types can produce interferon, neutrophils as one of important interferon source cells have been arousing growing attention, however the interferon production capacity of neutrophils in SLE and the regulation of neutrophils interferon production still remain unclear. Many long noncoding RNAs (lncRNAs) have been identified abnormally expressed in SLE that act on multiple signal pathways, we presume that there could be a role of lncRNAs in neutrophils interferon production regulation.

Methods: Interferon production was measured by qPCR and ISRE reporter gene assay, neutrophils interferon production capacity enhanced after interferon prime. We aimed to find out LncRNA that work in it. RNA-seq was performed in two sets of samples, interferon stimulated neutrophils samples and SLE versus healthy controls neutrophils samples. LncRNA-CMPK2 was screened out by cross-reference the two RNA-seq results. Expression of lncRNA-CMPK2 was knocked down in primary neutrophils using antisense oligos (ASO) by electroporation. To dissect the mechanism that lncRNA-CMPK2 act on TLR7/8 pathway interferon production, western blot was conducted to measure expression of key molecules in this pathway.

Results: 1. Neutrophils from SLE patients produced two fold more interferon than that from healthy controls by TLR7/8 agonist R848 stimulation. 2. Neutrophils interferon production capacity enhanced after interferon prime. 3. LncRNA-CMPK2 highly expressed in SLE neutrophils, it was the top 2 differently expressed lncRNA in lupus versus healthy controls and was also among the top significantly interferon stimulated lncRNAs according to the two sets of RNA-seq profiling. 4. LncRNA-CMPK2 expression level correlated with lupus interferon score and disease activity. 5. Knockdown of LncRNA-CMPK2 in neutrophils can attenuate interferon production. The mechanism may rely on reducing expression of IRAK4 and IRF7.

Conclusion: LncRNA-CMPK2 facilitates neutrophils interferon production in lupus. Over expression status of lncRNA-CMPK2 may provide new understanding of high interferon in the disease, targeting lncRNA-CMPK2 could probably help to control high interferon level in lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abnormal-expression-of-long-noncoding-rna-lncrna-cmpk2-facilitates-neutrophils-interferon-production-by-tlr78-agonist-stimulation-in-sle/