NOD2-Induced IκBζ Mediates a Protective Host Response against Epicutaneous Staphylococcus aureus Infection
IκBζ, an atypical and largely unknown member of the IκB family, is a transcriptional coactivator of selective immune functions. In this study, we investigated the role of keratinocyte-derived IκBζ upon infection with a multidrug-resistant Staphylococcus aureus strain. Infection of keratinocytes rapidly induced IκBζ expression, leading to an elevated expression of antimicrobial peptides, IL-17/IL-36-responsive genes, and proteins involved in skin barrier function. Conversely, loss of IκBζ resulted in increased S aureus internalization, epidermal tissue damage, and severe skin infections in vivo. This impaired host defense upon IκBζ depletion was characterized by reduced antimicrobial peptide expression and diminished recruitment of neutrophils and CD4<sup>+</sup> T cells. Importantly, S aureus-induced IκBζ expression required the internalization of the bacteria and its sensing by the intracellular receptor NOD2, which triggered IκBζ and its target gene expression. Thus, we identified NOD2-IκBζ signaling as a key pathway mediating a protective host defense against pathogenic S aureus infections in the skin.
Authors
- Edoardo Mazza (ORCID: https://orcid.org/0000-0001-9427-4157)
- Carsten Deppermann (ORCID: https://orcid.org/0000-0003-3740-8635)
- Antonia Kolb (ORCID: https://orcid.org/0009-0001-2790-9551)
- Enrico Focaccia (ORCID: https://orcid.org/0000-0001-9913-3492)
- Daniela Kramer (ORCID: https://orcid.org/0000-0002-3451-6182)
- Francesca Bork (ORCID: https://orcid.org/0000-0002-5073-4243)
- Martina Casari (ORCID: https://orcid.org/0000-0001-7137-5588)
- Alexander N.R. Weber (ORCID: https://orcid.org/0000-0002-8627-7056)
- Miriam Wittmann (ORCID: https://orcid.org/0000-0003-2328-4926)
- Klaus Schulze‐Osthoff (ORCID: https://orcid.org/0000-0003-1443-2720)
- Berenice Fischer (ORCID: https://orcid.org/0009-0004-1330-7156)
- Birgit Schittek (ORCID: https://orcid.org/0000-0003-0081-2001)
- Matthias Klein (ORCID: https://orcid.org/0000-0001-9064-6865)
- Tanja Kübelbeck (ORCID: https://orcid.org/0009-0000-7719-2571)
- Dagmar Löck
- Franziska Engelmann
Institutions
- Johannes Gutenberg University Mainz (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Journal of Investigative Dermatology
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1016/j.jid.2025.04.036
- Citations
- 1
- Primary Topic
- Antimicrobial Resistance in Staphylococcus
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Boehringer Ingelheim Stiftung