GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE314nnn/GSE314010/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314010GEOGSEfalseInterleukin-36 upregulated type-I interferon responses in systemic lupus erythematosis by promoting the accumulation of self-nucleic acidsSeveral studies have reported an up-regulation of interleukin (IL)-36 in the serum of patients with systemic lupus erythematosus (SLE). Here, we sought to define the mechanisms whereby IL-36 may contribute to the over-activation of type I Interferon (IFN) responses observed in SLE. We carried out single-cell (sc)RNA-seq in healthy peripheral blood mononuclear cells treated with IL-36 (n=5 donors). We compared the genes and transcriptional networks that were induced by IL-36 with those that were upregulated in a published SLE scRNA-seq dataset (n=33 cases and 11 controls). In follow-up studies, we validated the effects of IL-36 on monocytes by real-time PCR (n=9 donors) and flow-cytometry (n=6). Classical monocytes were the immune population most affected by IL-36 treatment (n=203 Differentially Expressed Genes). In these cells, IL-36 upregulated transcriptional networks (regulons) driven by IRF7, a key activator of type I IFN responses. A similar upregulation of IRF7 regulons was observed in the monocytes of SLE cases, where measurements of IL-36 and IRF7 activity were significantly correlated (r=0.35, P=0.02). Follow-up studies of human monocytes showed that IL-36 downregulates multiple RNAse genes (RNASE1, RNASE6, RNASET2). IL-36 treatment also increased the percentage of apoptotic cells (45% vs 37% in untreated cells; P=0.001), which are a critical source of self-nucleic acids. We find that IL-36 promotes monocyte apoptosis while downregulating self-nucleic acid clearance. Thus, IL-36 contributes to the accumulation of self-nucleic acids, a key driver of type I IFN responses in SLE.2026/03/12GSE314010GSM9379783GSM9379785GSM9379784GSM9379790GSM9379792GSM9379791GSM9379787GSM9379786GSM9379789GSM937978820301314010Homo sapiens[41607774]