In Vitro Effects of Sulforaphane on Interferon-Driven Inflammation and Exploratory Evaluation in Two Healthy Volunteers.

Elena Genova,Alberto Tommasini,Gabriele Stocco,Alessandra Tesser,Giuliana Decorti,Maura Apollonio

doi:10.3390/molecules26123602

Elena Genova, Alberto Tommasini + Show 4 more

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https://doi.org/10.3390/molecules26123602

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Abstract

Interferonopathies are rare genetic conditions defined by systemic inflammatory episodes caused by innate immune system activation in the absence of pathogens. Currently, no targeted drugs are authorized for clinical use in these diseases. In this work, we studied the contribution of sulforaphane (SFN), a cruciferous-derived bioactive molecule, in the modulation of interferon-driven inflammation in an immortalized human hepatocytes (IHH) line and in two healthy volunteers, focusing on STING, a key-component player in interferon pathway, interferon signature modulation, and GSTM1 expression and genotype, which contributes to SFN metabolism and excretion. In vitro, SFN exposure reduced STING expression as well as interferon signature in the presence of the pro-inflammatory stimulus cGAMP (cGAMP 3 h vs. SFN+cGAMP 3 h p value < 0.0001; cGAMP 6 h vs. SFN+cGAMP 6 h p < 0.001, one way ANOVA), restoring STING expression to the level of unstimulated cells. In preliminary experiments on healthy volunteers, no appreciable variations in interferon signature were identified after SFN assumption, while only in one of them, presenting the GSTM1 wild type genotype related to reduced SFN excretion, could a downregulation of STING be recorded. This study confirmed that SFN inhibits STING-mediated inflammation and interferon-stimulated genes expression in vitro. However, only a trend towards the downregulation of STING could be reproduced in vivo. Results obtained have to be confirmed in a larger group of healthy individuals and in patients with type I interferonopathies to define if the assumption of SFN could be useful as supportive therapy.

Highlights

The mechanisms behind inflammatory diseases are complex and various, making it difficult to find targeted therapies for patients
One of the most used set of interferon-stimulated genes (ISGs) for interferon signature assessment was proposed by Crow and his group [10], who defined the over-expression of six ISGs (IFI27, IFI44L, IFIT1, ISG15, RSAD2, and SIGLEC1) in a cohort of Aicardi-Goutières syndrome (AGS) patients compared to healthy controls
In this work we studied the effect of SFN on interferon inflammation induced by cGAMP treatment, using a healthy immortalized human hepatocytes (IHH) cell line, focusing on STING and interferon signature modulation

Summary

Introduction

The mechanisms behind inflammatory diseases are complex and various, making it difficult to find targeted therapies for patients. In the last ten years, a set of genetic diseases characterized by a defective regulation of type I interferons production, the so-called interferonopathies, were identified, which often showed poor responses to conventional anti-inflammatory drugs, including biologics and glucocorticoids. The assessment of interferon-mediated inflammation in these disorders relies on indirect assays, performed on peripheral blood cells, that present transcriptional changes related to their autocrine or paracrine exposition to high concentration of interferons [11]. One of these approaches consists in the relative quantification of a set of interferon-stimulated genes (ISGs), the so-called interferon signature. The validation of this score for the detection of monogenic interferonopathies made it preferred by centers involved in the screening and diagnosis of these rare conditions

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