Platelet-activating factor and protease-activated receptor 2 cooperate to promote neutrophil recruitment and lung inflammation through nuclear factor-kappa B transactivation.

Autor: Silva IS; Laboratory of Inflammation and Proteases, Department of Pharmacology, Institute of Biological Sciences (ICB), Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil., Almeida AD; Laboratory of Inflammation and Proteases, Department of Pharmacology, Institute of Biological Sciences (ICB), Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil., Lima Filho ACM; Department of Physiology and Biophysics, ICB/UFMG, Belo Horizonte, Minas Gerais, Brazil., Fernandes-Braga W; Laboratory of Atherosclerosis and Nutritional Biochemistry (LABIN-UFMG), Department of Biochemistry and Immunology, ICB/UFMG, Belo Horizonte, Minas Gerais, Brazil., Barra A; Laboratory of Inflammation and Proteases, Department of Pharmacology, Institute of Biological Sciences (ICB), Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil., Oliveira HMC; Department of Morphology, ICB/UFMG, Belo Horizonte, Minas Gerais, Brazil., Cassali GD; Department of Pathology, ICB/UFMG, Belo Horizonte, Minas Gerais, Brazil., Capettini LSA; Laboratory of Vascular Biology, Department of Pharmacology, ICB/UFMG, Belo Horizonte, Minas Gerais, Brazil., Menezes GB; Department of Morphology, ICB/UFMG, Belo Horizonte, Minas Gerais, Brazil., Alvarez-Leite JI; Laboratory of Atherosclerosis and Nutritional Biochemistry (LABIN-UFMG), Department of Biochemistry and Immunology, ICB/UFMG, Belo Horizonte, Minas Gerais, Brazil., Leite MF; Department of Physiology and Biophysics, ICB/UFMG, Belo Horizonte, Minas Gerais, Brazil., Klein A; Laboratory of Inflammation and Proteases, Department of Pharmacology, Institute of Biological Sciences (ICB), Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil. klein@ufmg.br.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Dec 07; Vol. 13 (1), pp. 21637. Date of Electronic Publication: 2023 Dec 07.
DOI: 10.1038/s41598-023-48365-1
Abstrakt: Although it is well established that platelet-activated receptor (PAF) and protease-activated receptor 2 (PAR2) play a pivotal role in the pathophysiology of lung and airway inflammatory diseases, a role for a PAR2-PAFR cooperation in lung inflammation has not been investigated. Here, we investigated the role of PAR2 in PAF-induced lung inflammation and neutrophil recruitment in lungs of BALB/c mice. Mice were pretreated with the PAR2 antagonist ENMD1068, PAF receptor (PAFR) antagonist WEB2086, or aprotinin prior to intranasal instillation of carbamyl-PAF (C-PAF) or the PAR2 agonist peptide SLIGRL-NH 2 (PAR2-AP). Leukocyte infiltration in bronchoalveolar lavage fluid (BALF), C-X-C motif ligand 1 (CXCL)1 and CXCL2 chemokines, myeloperoxidase (MPO), and N-acetyl-glycosaminidase (NAG) levels in BALF, or lung inflammation were evaluated. Intracellular calcium signaling, PAFR/PAR2 physical interaction, and the expression of PAR2 and nuclear factor-kappa B (NF-КB, p65) transcription factor were investigated in RAW 264.7 cells stimulated with C-PAF in the presence or absence of ENMD1068. C-PAF- or PAR2-AP-induced neutrophil recruitment into lungs was inhibited in mice pretreated with ENMD1068 and aprotinin or WEB2086, respectively. PAR2 blockade impaired C-PAF-induced neutrophil rolling and adhesion, lung inflammation, and production of MPO, NAG, CXCL1, and CXCL2 production in lungs of mice. PAFR activation reduced PAR2 expression and physical interaction of PAR2 and PAFR; co-activation is required for PAFR/PAR2 physical interaction. PAR2 blockade impaired C-PAF-induced calcium signal and NF-κB p65 translocation in RAW 264.7 murine macrophages. This study provides the first evidence for a cooperation between PAFR and PAR2 mediating neutrophil recruitment, lung inflammation, and macrophage activation.
(© 2023. The Author(s).)
Databáze: MEDLINE
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