Protease activated-receptor 2 is necessary for neutrophil chemorepulsion induced by trypsin, tryptase, or dipeptidyl peptidase IV

Abstract

Compared to neutrophil chemoattractants, relatively little is known about the mechanism neutrophils use to respond to chemorepellents. We previously found that the soluble extracellular protein dipeptidyl peptidase IV (DPPIV) is a neutrophil chemorepellent. In this report, we show that an inhibitor of the protease activated receptor 2 (PAR2) blocks DPPIV-induced human neutrophil chemorepulsion, and that PAR2 agonists such as trypsin, tryptase, 2f-LIGRL, SLIGKV, and AC55541 induce human neutrophil chemorepulsion. Several PAR2 agonists in turn block the ability of the chemoattractant fMLP to attract neutrophils. Compared to neutrophils from male and female C57BL/6 mice, neutrophils from male and female mice lacking PAR2 are insensitive to the chemorepulsive effects of DPPIV or PAR2 agonists. Acute respiratory distress syndrome (ARDS) involves an insult-mediated influx of neutrophils into the lungs. In a mouse model of ARDS, aspiration of PAR2 agonists starting 24 h after an insult reduce neutrophil numbers in the bronchoalveolar lavage (BAL) fluid, as well as the post-BAL lung tissue. Together, these results indicate that the PAR2 receptor mediates DPPIV-induced chemorepulsion, and that PAR2 agonists might be useful to induce neutrophil chemorepulsion.

An endogenous chemorepellent directs cell movement by inhibiting pseudopods at one side of cells

“…, 2018). The AprA-related neutrophil chemorepellent DPPIV also uses a G protein–coupled receptor to repel cells (White et al. , 2018).…”

“…An orthologue of AprA, dipeptidyl peptidase IV (DPPIV), acts as a chemorepellent for neutrophils (Herlihy et al. , 2013a, 2015, 2017; White et al. , 2018).…”

PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca2+ Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation

“…A few studies have in fact suggested an anti-inflammatory role of PAR2 but in a cellular context-dependent manner. For example, loss of PAR2 augmented lung inflammation induced by Pseudomonas aeruginosa primarily by activating macrophages, and a low dose of a PAR2 receptor agonist reduced neutrophil influx in a mouse model of ARDS (Moraes et al, 2008; White et al, 2018). …”

Extracellular signaling in Dictyostelium

“…Treatment with inhaled DPPIV prevented an increase in lung neutrophils in a mouse model of ARDS (Herlihy et al, 2013a), and localized injections of DPPIV decreased symptoms of arthritis in a mouse model (Herlihy et al, 2015). We then found that the DPPIV receptor is the proteaseactivated G protein-coupled receptor PAR 2, that PAR 2 agonists induce human neutrophil chemorepulsion, and when administered by aspiration into the airways, PAR 2 agonists show good efficacy at reducing the inappropriate influx of neutrophils into the lungs in a mouse model of ARDS (White et al, 2018). Together, this suggests…”