IκBζ is a mediator of NOD2 signaling in keratinocytes and epicutaneous S. aureus infection
Loading...
Date issued
Authors
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
Reuse License
Abstract
The atypical IκB protein IκBζ, encoded by NFKBIZ, constitutes a transcriptional co-factor of NF-κB, which is stimulus-dependently expressed in a variety of cell types. In this study, we investigated the role of IκBζ in epicutaneous Staphylococcus aureus (S. aureus) infection. By analyzing NFKBIZ-depleted, S. aureus-infected primary human keratinocytes and keratinocyte-specific IκBζ knockout mice, we uncovered that IκBζ expression in keratinocytes is critical to mediate a protective host response against S. aureus. This was due to the fact that IκBζ controlled the expression of a subset of S. aureus-responsive genes, being responsible for IL-17/IL-36 responses and the maintenance of the skin barrier.
Although keratinocytes also sense S. aureus with external TLR2 receptors, we further identified
S. aureus internalization and subsequent NOD2 activation as being mandatory for a Regnase-1-dependent expression of IκBζ and its pro-inflammatory target genes. Loss of IκBζ in vivo led to an impaired host defense, such as reduced secretion of antimicrobial peptides and less recruitment of innate and adaptive immune cells (neutrophils, monocytes, effector CD4+ T-cells, and γδ T-cells) to the side of infection, besides damage of skin tissue and stronger dissemination of bacteria. Therefore, this study discovered IκBζ as key player in the newly identified course of NOD2-IκBζ signaling, providing substantial support in the protection against pathogenic S. aureus skin infections.
Keywords: IκBζ, NFKBIZ, keratinocytes, NOD2, TLR2, MDP, Staphylococcus aureus, MRSA, antimicrobial peptides