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- Title
Enhanced GATA4 expression in senescent systemic lupus erythematosus monocytes promotes high levels of IFNα production.
- Authors
Taiga Kuga; Asako Chiba; Goh Murayama; Kosuke Hosomi; Tomoya Nakagawa; Yoshiyuki Yahagi; Daisuke Noto; Makio Kusaoi; Fuminori Kawano; Ken Yamaji; Naoto Tamura; Sachiko Miyake
- Abstract
Enhanced interferon a (IFNa) production has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We previously reported IFNa 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 IFNa 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. IFNa 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 IFNa 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 IFNa-positive SLE monocytes. Overexpression of GATA4 enhanced IFNa 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 IFNa related to GATA4 expression upon activation of the cGAS-STING pathway.
- Subjects
GENE expression; SYSTEMIC lupus erythematosus; CD14 antigen; MONOCYTES; CELLULAR aging; GATA proteins
- Publication
Frontiers in Immunology, 2024, p1
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2024.1320444