Topical Plant Polyphenols Prevent Type I Interferon Signaling in the Skin and Suppress Contact Hypersensitivity

Maria Carbone,Saveria Pastore,Daniela Lulli,Francesca Passarelli

doi:10.3390/ijms19092652

Maria Carbone, Saveria Pastore + Show 2 more

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https://doi.org/10.3390/ijms19092652

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Abstract

Human keratinocytes were recently shown to respond to anti-EGFR (epidermal growth factor receptor) drugs with activation of an interferon-κ-driven autocrine loop, leading to enhanced expression of innate antiviral effectors and of the pro-inflammatory chemokines CXCL10 (C-X-C motif chemokine 10) and CCL2 (C-C motif ligand 2). Here we showed active type I interferon signaling in the skin lesions of cancer patients undergoing treatment with the anti-EGFR drug cetuximab. Strong nuclear positivity for Interferon Regulatory Factor 1 and phosphorylated Signal Transducer and Activator of Transcription 1, enhanced interferon-κ expression and CXCL10 was associated to the epidermal compartment. Notably, 50 micromolar resveratrol and quercetin fully suppressed the low constitutive levels of type I interferon signaling and prevented its activation by the anti-EGFR cetuximab or gefitinib in cultured keratinocytes. In sensitized mice undergoing DNFB (2,4-dinitro-1-fluorobenzene)-induced contact hypersensitivity, local administration of gefitinib prior to elicitation further amplified hapten-induced type I interferon activation, tissue edema, and infiltration by T cells, whereas resveratrol or quercetin suppressed this inflammatory cascade. Overall, these data suggest that topical application of resveratrol or quercetin could be potentially effective in preventing pathological conditions due to overactivation of type I IFN (interferon)-driven circuits in the skin, including the inflammatory manifestations of anti-EGFR drug-induced skin-targeted toxicity.

Highlights

Interferons (IFNs) are pleiotropic, functionally related cytokines with a central role in the cellular antiviral defense [1]
In this study we showed activation of the IRF1/IFN-κ/P-STAT1 signaling cascade in the epidermal compartment of the inflammatory lesions manifesting in the skin of cancer patients treated with cetuximab
Activation of this pathway was evident in the skin of mice undergoing contact hypersensitivity, while local treatment with the anti-EGFR gefitinib prior to its elicitation led to a further accentuation of the epidermal positivity for nuclear IRF1 and P-STAT1, with enhanced IFN-κ, CXCL10, and CCL2 and the eventual aggravation of tissue edema and T cell infiltration

Summary

Introduction

Interferons (IFNs) are pleiotropic, functionally related cytokines with a central role in the cellular antiviral defense [1]. Via STAT-1 phosphorylation, IFN-κ receptor signaling further amplified the whole cascade, with enhanced expression of IRF1, a conspicuous number of antiviral effectors and a small cluster of pro-inflammatory mediators mainly comprising the chemokines CXCL10 and CCL2 [7]. Upregulation of these two chemokines is a common finding in inflammatory skin conditions where they promote massive T cell and monocyte recruitment, as previously confirmed in mouse models of DNFB (2,4-dinitro-1-fluorobenzene)-induced irritant and allergic contact hypersensitivity, with further aggravation due to concomitant EGFR pharmacological blockade [9,10]

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