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.