Vigilant Keratinocytes Trigger Pathogen-Associated Molecular Pattern Signaling in Response to Streptococcal M1 Protein

Abstract

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 pathogen-associated molecular pattern to release alarming inflammatory responses. We found that this interaction initiates an inflammatory intracellular signaling cascade involving the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal protein kinase and the subsequent induction and mobilization of the transcription factors NF-B and AP-1. We also determined the imprint of the inflammatory mediators released, such as interleukin-8 (IL-8), growth-related oncogene alpha, migration inhibitory factor, extracellular matrix metalloproteinase inducer, IL-1␣, IL-1 receptor a, and ST2, in response to streptococcal M1 protein. The expression of IL-8 is dependent on Toll-like receptor 2 activity and subsequent activation of the mitogen-activated protein kinases ERK and p38. Notably, this signaling seems to be distinct for IL-8 release, and it is not shared with the other inflammatory mediators. We conclude that keratinocytes participate in a proinflammatory manner in streptococcal pattern recognition and that expression of the chemoattractant IL-8 by keratinocytes constitutes an important protective mechanism against streptococcal M1 protein.

Group A streptococcal M protein activates the NLRP3 inflammasome

“…We hypothesize that in the latter case, macrophages are intrinsically stimulated by cellular processes such as metabolic activation elicited by the thioglycollate pre-treatment in our in vivo experiments, or alternatively that M1 may activate host-derived pro-inflammatory factors facilitating signal 1 priming. The later mechanism is consistent with recent studies, which have shown that keratinocytes recognize soluble M1 as a PAMP to release interleukin-8, growth-related oncogene-alpha, migration inhibitory factor, and other inflammatory response alarms 37 . Another study reported that M1 protein can synergize with heparin-binding protein to interact with TLR2 on monocytes and promote release of IL-1β and IL-6 38 , which differs somewhat from our findings showing no effect of M1 protein on IL-6 production in vitro or in vivo .…”

Hydrogels based on chitosan in tissue regeneration: How do they work? A mini review

“…This could be explained by two possible reasons. First, the chitosan‐based hydrogels were able to kill bacteria, inhibiting the overactivation of the inflammatory response induced by pathogen‐associated molecular patterns . Second, they could regulate macrophages to be M2 phenotype through the activation of the p‐STAT6 signaling pathway.…”

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“…TGF‐β1 also regulates the expression of extracellular matrix proteins, including fibronectin and αβ integrins, and TGF‐β1 signaling has been shown to enhance GAS invasion of epithelial cells, suggesting that it may play a role in promoting bacterial colonization. In response to GAS infection, epithelial cells also secrete neutrophil chemoattractants, such as IL‐8, with this process likely to be an important protective mechanism elicited by epithelial cells during GAS pharyngitis …”