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

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

  • Satoh TK Department of Dermatology, University of Zürich, Zürich, Switzerland.
  • Mellett M Department of Dermatology, University of Zürich, Zürich, Switzerland.
  • Meier-Schiesser B Department of Dermatology, University of Zürich, Zürich, Switzerland.
  • Fenini G Department of Dermatology, University of Zürich, Zürich, Switzerland.
  • Otsuka A Department of Dermatology, Kyoto University, Kyoto, Japan.
  • Beer HD Department of Dermatology, University of Zürich, Zürich, Switzerland.
  • Rordorf T Clinic for Oncology, University Hospital Zürich, Zürich, Switzerland.
  • Maul JT Department of Dermatology, University of Zürich, Zürich, Switzerland.
  • Hafner J Department of Dermatology, University of Zürich, Zürich, Switzerland.
  • Navarini AA Department of Dermatology, University of Zürich, Zürich, Switzerland.
  • Contassot E Department of Dermatology, University of Zürich, Zürich, Switzerland.
  • French LE Department of Dermatology, University of Zürich, Zürich, Switzerland.
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  • 2019-12-06
Published in:
  • The Journal of clinical investigation. - 2020
Cytokines
Dermatology
Inflammation
Molecular biology
Skin
Animals
ErbB Receptors
Humans
Interleukin-1
Keratinocytes
Kruppel-Like Transcription Factors
MAP Kinase Signaling System
Mice
Mice, Knockout
NF-kappa B
Propionibacteriaceae
Skin Diseases, Bacterial
English 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.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/82419
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