1. Academic Validation
  2. Excess filaggrin in keratinocytes is removed by extracellular vesicles to prevent premature death and this mechanism can be hijacked by Staphylococcus aureus in a TLR2-dependent fashion

Excess filaggrin in keratinocytes is removed by extracellular vesicles to prevent premature death and this mechanism can be hijacked by Staphylococcus aureus in a TLR2-dependent fashion

  • J Extracell Vesicles. 2023 Jun;12(6):e12335. doi: 10.1002/jev2.12335.
Adrian Kobiela 1 Lilit Hovhannisyan 1 Paulina Jurkowska 1 Jorge Bernardino de la Serna 2 3 Aleksandra Bogucka 4 Milena Deptuła 5 Argho Aninda Paul 1 Kinga Panek 1 Ewa Czechowska 1 Michał Rychłowski 6 Aleksandra Królicka 7 Jacek Zieliński 8 Susanne Gabrielsson 9 10 Michał Pikuła 5 Magdalena Trzeciak 11 Graham S Ogg 12 Danuta Gutowska-Owsiak 1 12
Affiliations

Affiliations

  • 1 Experimental and Translational Immunology Group, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, University of Gdansk, Gdansk, Poland.
  • 2 National Heart and Lung Institute, Imperial College London, London, UK.
  • 3 Central Laser Facility, Rutherford Appleton Laboratory, Medical Research Council-Research Complex at Harwell, Science and Technology Facilities Council, UK.
  • 4 The Mass Spectrometry Laboratory, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, Gdansk, Poland.
  • 5 Laboratory of Tissue Engineering and Regenerative Medicine, Department of Embryology, Medical University of Gdansk, Gdansk, Poland.
  • 6 Laboratory of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, University of Gdansk, Gdansk, Poland.
  • 7 Laboratory of Biologically Active Compounds, Intercollegiate Faculty of Biotechnology of University of Gdansk and Medical University of Gdansk, University of Gdansk, Gdansk, Poland.
  • 8 Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland.
  • 9 Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
  • 10 Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
  • 11 Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk, Poland.
  • 12 Medical Research Council (MRC) Human Immunology Unit, Medical Research Council (MRC) Weatherall Institute of Molecular Medicine, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Abstract

Filaggrin (FLG) protein is indispensable for multiple aspects of the epidermal barrier function but its accumulation in a monomeric filaggrin form may initiate premature keratinocytes death; it is unclear how filaggrin levels are controlled before the formation of storing keratohyalin granules. Here we show that keratinocyte-secreted small extracellular vesicles (sEVs) may contain filaggrin-related cargo providing a route of eliminating excess filaggrin from keratinocytes; blocking of sEV release has cytotoxic effects on those cells. Filaggrin-containing sEVs are found in plasma in both healthy individuals and atopic dermatitis patients. Staphylococcus aureus (S. aureus) enhances packaging and secretion of filaggrin-relevant products within the sEVs for enhanced export via a TLR2-mediated mechanism which is also linked to the ubiquitination process. This filaggrin removal system, preventing premature keratinocyte death and epidermal barrier dysfunction, is exploited by S. aureus which promotes filaggrin elimination from the skin that could help safeguard Bacterial growth.

Keywords

Staphylococcus aureus; atopic dermatitis; bacteria; exosomes; extracellular vesicles; filaggrin; keratinocyte.

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