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IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes
Takashi K. Satoh, … , Emmanuel Contassot, Lars E. French
Takashi K. Satoh, … , Emmanuel Contassot, Lars E. French
Published December 5, 2019
Citation Information: J Clin Invest. 2020;130(3):1417-1430. https://doi.org/10.1172/JCI128678.
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Research Article Dermatology Inflammation Article has an altmetric score of 6

IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes

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Abstract

Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity. We provide molecular and translational evidence that EGFRi/MEKi in concert with the skin commensal bacterium Cutibacterium acnes act synergistically to induce IL-36γ in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36γ expression was the combined result of C. acnes–induced NF-κB activation and EGFRi/MEKi–mediated expression of the transcription factor Krüppel-like factor 4 (KLF4), due to the presence of both NF-κB and KLF4 binding sites in the human IL-36γ gene promoter. EGFRi/MEKi increased KLF4 expression by blockade of the EGFR/MEK/ERK pathway. These results provide an insight into understanding the pathological mechanism of the acneiform skin toxicities induced by EGFRi/MEKi and identify IL-36γ and the transcription factor KLF4 as potential therapeutic targets.

Authors

Takashi K. Satoh, Mark Mellett, Barbara Meier-Schiesser, Gabriele Fenini, Atsushi Otsuka, Hans-Dietmar Beer, Tamara Rordorf, Julia-Tatjana Maul, Jürg Hafner, Alexander A. Navarini, Emmanuel Contassot, Lars E. French

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Figure 1

Increased production of IL-36γ in primary keratinocytes and lesional skin of patients suffering from acneiform eruptions in response to EGFR inhibition and C. acnes.

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Increased production of IL-36γ in primary keratinocytes and lesional ski...
(A) Gene expression profiling from lesional skin of 5 patients and 5 healthy controls (HC). Heatmap of the top 12 most differentially expressed genes ranked from lowest false discovery rate (FDR) and 12 selected genes are shown. (B) Quantitative PCR (qPCR) of mRNA from lesional skin samples of 10 EGFR inhibitor–treated patients with acneiform eruption and 10 healthy control skin biopsies. Data represent mean ± SD. (C) Immunohistochemical staining with goat anti–IL-36γ antibody of formalin-fixed, paraffin-embedded skin sections of acneiform eruption patient and normal donors. Scale bars: 100 μm. Pictures are representative of 5 patients and 5 healthy individuals. (D) PHKs were exposed to erlotinib (EGFR inhibitor, 1 μM) and C. acnes (MOI of 10) for 6 hours. Total RNA was analyzed by qPCR. Data represent mean ± SEM (n = 3). (E) PHKs were exposed to erlotinib (1 μM) or C. acnes (MOI of 10) or both for 24 hours. Cell lysates were analyzed by Western blotting using specific antibodies against IL-36γ and β-actin. Blots were run contemporaneously with the same protein samples. (F) PHKs were exposed to erlotinib (1 μM) and Pam3CSK4 (5 μg/mL). IL-36γ secretion was measured by ELISA in culture supernatants. Data represent mean ± SEM (n = 3). (G) Ex vivo skin explants were exposed to erlotinib (1 μM), Pam3CSK4 (5 μg/mL), and/or human IL-36Ra (1 μg/mL). The skin samples were then analyzed by qPCR. Data represent mean ± SEM (n = 4). Data were analyzed with 2-tailed unpaired t test (B), and 1-way ANOVA followed by Dunnett’s (D and F) or Tukey’s multiple-comparisons test (G). *P < 0.05; **P < 0.01; ***P < 0.001. Data are representative of 3 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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