Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo.

Mucosal Immunol

Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, USA.

Published: January 2010

AI Article Synopsis

  • Toll-like receptors (TLRs) and proteinase-activated receptors (PARs) act as crucial sensors in the innate immune response of mucosal epithelial cells, showing that they can interact and cooperate with each other.
  • Research demonstrates that PAR(2) works alongside TLR2, TLR3, and TLR4 to activate immune signaling, but it negatively impacts the antiviral response of TLR3 by suppressing key gene expressions related to the immune response.
  • Animal studies indicate that mice lacking PAR(2) or TLR4 are less susceptible to certain viral infections, supporting the idea of a complex interaction and cooperativity between these receptors in modulating immune responses.

Article Abstract

Toll-like receptors (TLRs) and proteinase-activated receptors (PARs) function as innate immune biosensors in mucosal epithelial cells (ECs). We previously reported the functional and physical interactions between TLR4 and PAR(2). We have extended these findings herein by showing the cooperation between PAR(2) and TLR2, TLR3, or TLR4 for activation of nuclear factor-kappaB-dependent signaling in mucosal EC lines. In contrast, activation of PAR(2) negatively regulated TLR3-dependent antiviral pathway, blunting the expression of TLR3/interferon regulatory factor-3 (IRF-3)-driven genes, as well as activation of IRF-3 and STAT1. Consistent with these in vitro observations, PAR(2)(-/-) and TLR4(-/-) mice, which were refractory to footpad edema induced by PAR(2) agonist peptide, were protected from mouse-adapted H1N1 influenza A virus-induced lethality when compared to wild-type (WT) mice. These data support and extend our recently described, novel model of PAR(2)-TLR4 "receptor cooperativity" and highlight the complexity of signaling integration between heterologous innate immune biosensors.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851245PMC
http://dx.doi.org/10.1038/mi.2009.120DOI Listing

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