{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T04:11:35Z","timestamp":1792555895332,"version":"4.5.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T00:00:00Z","timestamp":1711584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Enhanced interferon \u03b1 (IFN\u03b1) production has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We previously reported IFN\u03b1 production by monocytes upon activation of the stimulator of IFN genes (STING) pathway was enhanced in patients with SLE. We investigated the mechanism of enhanced IFN\u03b1 production in SLE monocytes. Monocytes enriched from the peripheral blood of SLE patients and healthy controls (HC) were stimulated with 2\u20323\u2032-cyclic GAMP (2\u20323\u2032-cGAMP), a ligand of STING. IFN\u03b1 positive\/negative cells were FACS-sorted for RNA-sequencing analysis. Gene expression in untreated and 2\u20323\u2032-cGAMP-stimulated SLE and HC monocytes was quantified by real-time PCR. The effect of GATA binding protein 4 (GATA4) on IFN\u03b1 production was investigated by overexpressing GATA4 in monocytic U937 cells by vector transfection. Chromatin immunoprecipitation was performed to identify GATA4 binding target genes in U937 cells stimulated with 2\u20323\u2032-cGAMP. Differentially expressed gene analysis of cGAS-STING stimulated SLE and HC monocytes revealed the enrichment of gene sets related to cellular senescence in SLE. CDKN2A, a marker gene of cellular senescence, was upregulated in SLE monocytes at steady state, and its expression was further enhanced upon STING stimulation. GATA4 expression was upregulated in IFN\u03b1-positive SLE monocytes. Overexpression of GATA4 enhanced IFN\u03b1 production in U937 cells. GATA4 bound to the enhancer region of IFIT family genes and promoted the expressions of IFIT1, IFIT2, and IFIT3, which promote type I IFN induction. SLE monocytes with accelerated cellular senescence produced high levels of IFN\u03b1 related to GATA4 expression upon activation of the cGAS-STING pathway.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1320444","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T04:44:47Z","timestamp":1711601087000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Enhanced GATA4 expression in senescent systemic lupus erythematosus monocytes promotes high levels of IFN\u03b1 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