BRIEF RESEARCH REPORT article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
This article is part of the Research TopicCommunity Series in Molecular Characterisation of Autoimmune Diseases Volume IIView all articles
Interleukin-36 upregulates type-I interferon responses in systemic lupus erythematosus by promoting the accumulation of self-nucleic acids
Provisionally accepted
- 1King's College London, London, United Kingdom
- 2Boehringer Ingelheim, Biberach, Germany
- 3Queen Mary University of London, London, United Kingdom
- 4University of British Columbia, Vancouver, Canada
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Introduction: 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. Methods: 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). Results: 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). Experimental follow-up studies in human monocytes showed that IL-36 downregulates multiple RNAse genes (RNASE1, RNASE6, RNASET2). IL-36 treatment of monocytes 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. Conclusion: 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.
Keywords: IL-36, IRF7, RNase, SLE, Type-I IFN
Received: 17 Oct 2025; Accepted: 22 Dec 2025.
Copyright: © 2025 Welsh, McCluskey, Baum, Lewis and Capon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Francesca Capon
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