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

ABSTRACT: Several 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314010 | GEO | 2026/03/12

REPOSITORIES: GEO

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Project description:NYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade C env, gag, pol, and nef genes (NYVAC-C) with single or double deletions of genes encoding type I (B19R) or type II (B8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with the B19R deletion (NYVAC-C- B19R), or NYVAC-C with B8R and B19R deletions (NYVAC-C- B8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C- B19R and NYVAC-C- B8RB19R than with NYVAC-C. Deletion of B8R and B19R resulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C- B8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF-], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C- B19R as well as a strong inflammasome response (caspase-1 and IL-1 ) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion of B8R and B19R was organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C- B8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4 T cell response than monocytes infected with NYVAC-C or NYVAC-C- B19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1 and make it an attractive candidate HIV vaccine vector. Primary Human monocytes from 5 donors were incubated with each following vectors nyvacdb, nyvadb19r, nyvaccdb8rb19r_6h, untreated control and collected at 6h.

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

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