Vigilant Keratinocytes Trigger PAMP Signaling in Response to Streptococcal M1 Protein.

The human skin exerts many functions in order to maintain its barrier integrity and protect the host from invading microorganisms. One such pathogen is Streptococcus pyogenes, which can cause a variety of superficial skin wounds that may eventually progress into invasive deep soft tissue infections. Here we show that keratinocytes recognize soluble M1 protein, a streptococcal virulence factor, as a PAMP to release alarming inflammatory responses. We found that this interaction initiates an inflammatory intracellular signaling cascade involving the activation of mitogen-activated kinases, ERK, p38 and JNK, and the subsequent induction and mobilization of the transcription factors NF-κB and AP-1. We also determined the imprint of inflammatory mediators released, such as IL-8, GROα, MIF, EMMPRIN, IL-1α, IL-1Ra, and ST2 in response to streptococcal M1 protein. The expression of IL-8 is dependent on TLR2 activity and subsequent activation of the MAP kinases ERK and p38. Notably this signaling seems distinct for IL-8 release and it is not shared with the other inflammatory mediators. We conclude that keratinocytes participate pro-inflammatory in streptococcal pattern recognition and that expression of the chemoattractant IL-8 by keratinocytes constitutes an important protective mechanism against streptococcal M1 protein.