{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T12:48:11Z","timestamp":1768308491580,"version":"3.49.0"},"reference-count":15,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012041","name":"Versus Arthritis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 (\n                      <jats:italic>RNASE1, RNASE6, RNASET2<\/jats:italic>\n                      ). 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1727524","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T06:30:17Z","timestamp":1768285817000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Interleukin-36 upregulates type-I interferon responses in systemic lupus erythematosus by promoting the accumulation of self-nucleic acids"],"prefix":"10.3389","volume":"16","author":[{"given":"Emma J.","family":"Welsh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"McCluskey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Baum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myles J.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Capon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"102361","DOI":"10.1016\/j.autrev.2019.102361","article-title":"Monogenic lupus: Dissecting heterogeneity","volume":"18","author":"Omarjee","year":"2019","journal-title":"Autoimmun 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