Enhanced GATA4 expression in senescent systemic lupus erythematosus monocytes promotes high levels of IFNα production.

Autor:	Kuga T; Department of Immunology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.; Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Chiba A; Department of Immunology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Murayama G; Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Hosomi K; Department of Immunology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Nakagawa T; Department of Immunology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Yahagi Y; Department of Immunology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.; Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Noto D; Department of Immunology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Kusaoi M; Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Kawano F; Graduate School of Health Sciences, Matsumoto University, Matsumoto, Nagano, Japan., Yamaji K; Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Tamura N; Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan., Miyake S; Department of Immunology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Mar 28; Vol. 15, pp. 1320444. Date of Electronic Publication: 2024 Mar 28 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1320444
Abstrakt:	Enhanced interferon α (IFNα) production has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We previously reported IFNα 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 IFNα production in SLE monocytes. Monocytes enriched from the peripheral blood of SLE patients and healthy controls (HC) were stimulated with 2'3'-cyclic GAMP (2'3'-cGAMP), a ligand of STING. IFNα positive/negative cells were FACS-sorted for RNA-sequencing analysis. Gene expression in untreated and 2'3'-cGAMP-stimulated SLE and HC monocytes was quantified by real-time PCR. The effect of GATA binding protein 4 (GATA4) on IFNα 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 2'3'-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 IFNα-positive SLE monocytes. Overexpression of GATA4 enhanced IFNα 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 IFNα related to GATA4 expression upon activation of the cGAS-STING pathway. Competing Interests: NT received grants from Astellas, Asahi Kasei Pharma, AbbVie, Ayumi, Chugai, Eisai, Nippon Boehringer Ingelheim, Taisho and Tanabe Mitsubishi, and speaker’s fees from AbbVie, Asahi Kasei Pharma, AstraZeneca, Bristol Myers Squibb, Chugai, Eli Lilly Japan, GlaxoSmithKline, Novartis, and Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Kuga, Chiba, Murayama, Hosomi, Nakagawa, Yahagi, Noto, Kusaoi, Kawano, Yamaji, Tamura and Miyake.)
Databáze:	MEDLINE
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