Protease-activated receptor 4 plays a role in lipopolysaccharide-induced inflammatory mechanisms in murine...

The role of protease-activated receptor (PAR)4 in thrombin-induced platelet aggregation has been studied, and PAR4 blockade is thought to be useful as a new and promising approach in antiplatelet therapy in humans. In recent years, studies have been conducted to clarify the role of PAR4 in the host defense against invading microorganisms and pathogen-induced inflammation; however, to date, the role of PAR4 in mediating the LPS-induced inflammatory repertoire in macrophages remains to be elucidated. Here, we investigated the effects of the synthetic PAR4 agonist peptide (PAR4-AP) AYPGKF-NH₂ on the phagocytosis of zymosan-FITC particles; NO, ROS, and iNOS expression; and cytokine production in C57/BL6 macrophages cocultured with PAR4-AP/LPS. The PAR4-AP impaired LPS-induced and basal phagocytosis, which was restored by pharmacological PAR4 blockade. Coincubation with the PAR4-AP/LPS enhanced NO and ROS production and iNOS expression; decreased IL-10, but not TNF-α, in the culture supernatant; and increased translocation of the p65 subunit of the proinflammatory gene transcription factor NF-κ-B. Our results provide evidence for a complex mechanism and new approach by which PAR4 mediates the macrophage response triggered by LPS through counter-regulating the phagocytic activity of macrophages and innate response mechanisms implicated in the killing of invading pathogens.