Abstract
The type 1 TNF-α receptor (TNFR1) has a central role in initiating both pro-inflammatory and pro-apoptotic signaling cascades in neutrophils. Considering that TNFR1 signals Staphylococcus aureus protein A (SpA), the aim of this study was to explore the interaction of this bacterial surface protein with neutrophils and keratinocytes to underscore the signaling pathways that may determine the fate of these innate immune cells in the infected tissue during staphylococcal skin infections. Using human neutrophils cultured in vitro and isogenic staphylococcal strains expressing or not protein A, we demonstrated that SpA is a potent inducer of IL-8 in neutrophils and that the induction of this chemokine is dependent on the SpA-TNFR1 interaction and p38 activation. In addition to IL-8, protein A induced the expression of TNF-α and MIP-1α highlighting the importance of SpA in the amplification of the inflammatory response. Protein A contributed to reduce neutrophil mortality prolonging their lifespan upon the encounter with S. aureus. Signaling initiated by SpA modulated the type of neutrophil cell death in vitro and during skin and soft tissue infections (SSTI) in vivo triggering the apoptotic pathway instead of necrosis. Moreover, SpA induced pro-inflammatory cytokines in keratinocytes, modulating their survival in vitro and preventing the exacerbated necrosis and ulceration of the epithelium during SSTI in vivo. Taken together, these results highlight the importance of the inflammatory signaling induced by protein A in neutrophils and skin epithelial cells. The ability of protein A to modulate the neutrophil/epithelial cell death program in the skin is of clinical relevance considering that lysis of neutrophils and epithelial cells will promote an intense inflammatory response and contribute to tissue damage, a non-desirable feature of complicated SSTI.
Highlights
Neutrophils are essential components of the innate immune response
IL-8 production was not observed when neutrophils were stimulated with Y14A (Figure 1A), a mutated Staphylococcus aureus protein A (SpA) unable to interact with TNFR1 [21] confirming that protein A signals through the TNFa receptor in neutrophils as well as we and other researchers have reported in other cell types [6, 9, 11]
Several types of death have been described after the encounter of S. aureus and the neutrophils [32], little is known about the bacterial products responsible for manipulating neutrophil signaling cascades and ultimate cell fate as well as the impact of the infection microenvironment
Summary
Neutrophils are essential components of the innate immune response. They constitute an abundant pool in the circulation and they are rapidly recruited into infection sites [1]. Neutrophils express a large number of cell surface receptors for the recognition of microbes as well as to sense the inflammatory microenvironment [2]. Among this last group are the TNFreceptor family members. The type 1 TNF-a receptor (TNFR1) has a central role in initiating both pro-inflammatory and pro-apoptotic signaling cascades in neutrophils depending on the molecules recruited to the receptor [4, 5]. The interaction of staphylococcal protein A with neutrophils, and the signaling cascades initiated by TNFR1 in these cells, has not yet been established
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call