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In the skin, a highly regulated interplay between keratinocytes, immune cells, and the skin microbiome provides a protective barrier against skin infections with Staphylococcus aureus (S. aureus). A disturbance of this balance can lead to increased S. aureus colonization of the skin, which is particularly evident in atopic dermatitis (AD), an inflammatory skin disorder with an impaired barrier function of the skin. The abundant presence of S. aureus on AD skin exacerbates inflammation and barrier defects in the skin. In order to develop effective treatments, it is crucial to understand how the immune system interacts in this scenario. Neutrophils, while essential for fighting S. aureus, may paradoxically create a favorable environment for its colonization in inflammatory skin conditions, particularly through interactions with keratinocytes and NET formation. However, the underlying mechanisms of this phenomenon remain unknown.
Therefore, this work aimed to provide a detailed mechanistic understanding of how S. aureus colonization is enhanced in inflamed skin through the actions of neutrophils and NETs. We have demonstrated that disruption of the skin barrier by tape-stripping enhances S. aureus colonization of the skin and the presence of neutrophils in the skin in an in vivo epicutaneous colonization model. Neutrophil depletion reduced this enhanced S. aureus colonization revealing a functional role for them in this scenario. Further in vitro investigations using a human co-culture system of primary human keratinocytes and neutrophils showed that neutrophils co-incubated with keratinocytes are primed for NET formation in response to S. aureus infection. We show that the increased presence of neutrophils and NETs causes oxidative stress in the skin, which triggers the secretion of HMGB1. Extracellular HMGB1 induces further oxidative stress in the skin and NET formation in infiltrating neutrophils, leading to the decreased expression of epidermal barrier proteins and increased S. aureus colonization of the skin. The clinical evidence of our study is supported by analyses showing increased levels of HMGB1, neutrophils and NETs in the skin of AD patients.
Since neutrophils possess immunomodulatory functions and are associated with the exacerbation of skin inflammation in a variety of skin diseases, we investigated how the interaction between keratinocytes and neutrophils in the skin affects the immune response to S. aureus skin infections. Using our in vitro co-culture model, we showed that co-culturing neutrophils with keratinocytes leads to a significant prolongation of neutrophil lifespan, mediated by secreted IL-8, which was associated with an increased activity of neutrophils against S. aureus. Furthermore, prolonged co-culture with neutrophils induced inflammation in keratinocytes, which was exacerbated by S. aureus infection. Notably, the skin commensal S. epidermidis reduced neutrophil-mediated skin inflammation in keratinocytes and induced apoptosis in activated neutrophils, suggesting a beneficial role of the skin microbiome in preventing excessive skin inflammation.
In conclusion, this work provides the intriguing finding that the interaction between neutrophils and keratinocytes plays a critical role in S. aureus skin infections in inflamed skin. First, a crosstalk between keratinocytes and neutrophils primes neutrophils for NET formation, which promotes S. aureus colonization of the skin by causing skin barrier defects in a ROS-dependent manner. Second, the interplay between neutrophils and keratinocytes exacerbates skin inflammation induced by S. aureus infection. Therefore, we propose that the blockade of the interaction between neutrophils, NETs, and keratinocytes could serve as a potential treatment approach for skin disorders associated with S. aureus colonization, such as AD. |
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