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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Microbial Immunology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1507989
This article is part of the Research Topic The Role of the Ubiquitin and Ubiquitin-Like Proteins in Bacterial and Parasitic Infections View all 5 articles

Ablation of the deubiquitinating enzyme cylindromatosis (CYLD) augments STAT1 mediated M1-macrophage polarization and fosters Staphylococcus aureus control

Provisionally accepted
Christina Schmidt Christina Schmidt 1Kunjan Harit Kunjan Harit 1Stephan Traidl Stephan Traidl 1Michael Naumann Michael Naumann 2Thomas Werfel Thomas Werfel 1Lennart Roesner Lennart Roesner 1Gopala Nishanth Gopala Nishanth 1*Dirk Schlüter Dirk Schlüter 1*
  • 1 Hannover Medical School, Hanover, Germany
  • 2 Otto von Guericke University Magdeburg, Magdeburg, Saxony-Anhalt, Germany

The final, formatted version of the article will be published soon.

    In atopic dermatitis (AD), lesional skin is frequently colonized by Staphylococcus (S.) aureus, which promotes clinical symptoms of the disease. The inflammatory milieu in the skin is characterized by a Th2-response, including M2-macrophages, which cannot eradicate S. aureus. Therefore, repolarization of macrophages towards M1-phenotype may foster control of S. aureus. Our data shows that the deubiquitinating enzyme cylindromatosis (CYLD) is strongly expressed in macrophages of AD patients and prevents the clearance of S. aureus. Mechanistically, CYLD impaired M1-macrophage polarization by K63-specific deubiquitination of STAT1 and activation of NF-B pathway via its interaction with TRAF6, NEMO and RIPK2. Inhibition of STAT1 and NF-κB, independently, abolished the differences between S. aureus-infected CYLD-deficient and -competent M1-macrophages. Infection of Cylddeficient and wildtype mice with S. aureus confirmed the protective CYLD function. Collectively, our study shows that CYLD impairs the control of S. aureus in macrophages of AD patients identifying CYLD as a potential therapeutic target.

    Keywords: Staphylococcus aureus, macrophage, CYLD, Ubiquitin, atopic dermatitis, STAT1, NF-B

    Received: 08 Oct 2024; Accepted: 07 Jan 2025.

    Copyright: © 2025 Schmidt, Harit, Traidl, Naumann, Werfel, Roesner, Nishanth and Schlüter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Gopala Nishanth, Hannover Medical School, Hanover, Germany
    Dirk Schlüter, Hannover Medical School, Hanover, Germany

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