Interleukin-36 upregulated type-I interferon responses in systemic lupus erythematosis by promoting the accumulation of self-nucleic acids

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.