Protease-activated receptor 4 plays a role in lipopolysaccharide-induced inflammatory mechanisms in murine macrophages
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ORIGINAL ARTICLE
Protease-activated receptor 4 plays a role in lipopolysaccharide-induced inflammatory mechanisms in murine macrophages A. Barra 1 & K. M. Freitas 2 & D. G. Marconato 3 & P. Faria-Pinto 3 & M. T. P. Lopes 2 & André Klein 1 Received: 25 June 2020 / Accepted: 29 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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. Keywords PAR4 . Protease-activated receptor-4 . Macrophage activation . LPS . Macrophage phagocytosis
Introduction The protease-activated receptor (PAR) family consists of four G protein-coupled receptors (PAR1–4) that are activated through the proteolytic and irreversible cleavage of a specific Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00210-02002014-w. * André Klein [email protected] 1
Laboratory of Pain and Inflammation, Department of Pharmacology, Institute of Biological Sciences (ICB), Federal University of Minas Gerais (UFMG), Av. Presidente Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-010, Brazil
2
Laboratory of Antitumoral Substances, Department of Pharmacology, ICB, UFMG, Belo Horizonte, MG, Brazil
3
Protein Structure and Function Study Laboratory, Department of Biochemistry, ICB, Federal University of Juiz de Fora (UFJF), Juiz de Fora, MG, Brazil
fragment of an amino group in the extracellular N-terminal domain of the receptor, exposing a novel anchored fragment that acts as a ligand to the second extracellular loop of the receptor itself, triggering downstream cellular signaling events (Vu et al. 1991; Hollenberg and Compton 2002). These receptors, with the exception of PAR3, can be pharmacologically
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