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

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 PAR₂. We have extended these findings herein by showing the cooperation between PAR₂ and TLR2, TLR3, or TLR4 for activation of nuclear factor-κB-dependent signaling in mucosal EC lines. In contrast, activation of PAR₂ 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, PAR₂^−/− and TLR4^−/− mice, which were refractory to footpad edema induced by PAR₂ 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 PAR₂–TLR4 “receptor cooperativity” and highlight the complexity of signaling integration between heterologous innate immune biosensors.