Serum IFNα2 levels are associated with disease activity and outperform IFN-I gene signature in a longitudinal childhood-onset SLE cohort

Wahadat, M. Javad; Qi, Hongchao; Helden-Meeuwsen, Cornelia G van; Huijser, Erika; Berg, Lotte van den; Dijk-Hummelman, Annette van; Göpfert, Jens; Heine, Anne; Verkaaik, Marleen; Schreurs, Marco W. J.; Dik, Willem A.; Kamphuis, Sylvia; Versnel, Marjan A.

doi:10.1093/rheumatology/keac698

Cited by 3 publications

(2 citation statements)

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“…IFNa has a critical role in the pathogenesis of lupus (1, 2). Elevated IFNa levels during periods of remission predicted flares in SLE patients (21,22), and elevated interferon-stimulated gene expressions preceded flares in SLE patients (23). These findings suggest that the upregulation of IFNa may be involved in the occurrence of flares in SLE patients.…”

Section: Discussionmentioning

confidence: 99%

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

Kuga,

Chiba,

Murayama

et al. 2024

Front. Immunol.

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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.

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Section: Discussionmentioning

confidence: 99%

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

Kuga,

Chiba,

Murayama

et al. 2024

Front. Immunol.

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show abstract

“…FIGURE: (A) Whole blood expression of IFN-stimulated genes (ISG) IFI44, IFI44L, IFIT1, IFIT3 and MxA was quantified from PAXgene Blood RNA tubes by RT-PCR; ISG score was calculated as described previously.4,5 For calculation of relative gene expressions, samples were normalized to expression of the household gene Abl.IFN score was calculated according to the following formula: = P ((log (2^-(CT-Abl))-M HC )/SD HC ) using an in house healthy control (HC) dataset. Scores higher than 9.4 are considered as positive.…”

mentioning

confidence: 99%