Measurement of Respiratory Burst Products, Released or Retained, During Activation of Professional Phagocytes

Barbadin selectively modulates FPR2-mediated neutrophil functions independent of receptor endocytosis

“…Given that Barbadin binds to AP2 and prevents the AP2/-arrestin interaction, our results indicate a role for AP2 in FPR2-mediated ROS release from human neutrophils. a large number of ligands belonging to different chemical classes [5][6][7]. Depending on the agonists examined, the signals generated by FPR2 mediate primarily pro-inflammatory…”

“…Neutrophils, the most abundant leukocytes in human peripheral blood, form the frontline of our innate host immune defense, and are rapidly recruited from the circulation to damaged or infected body tissues, where they contribute to bacterial clearance and tissue repair [1][2][3][4]. The formyl peptide receptor 2 (FPR2), belonging to the family of G protein-coupled receptors (GPCRs), regulates directional neutrophil migration (chemotaxis), granule secretion (degranulation), formation of F-actin filaments (through polymerization of G-actin), and activation of the reactive oxygen species (ROS) producing NADPH-oxidase [3,5,6]. FPR2 recognizes not only N-formyl peptides of both bacterial and host mitochondrial origin, but also Neutrophil surface expression of FPR2 or CD11b was examined by flow cytometry.…”

“…Taken together, our data demonstrate that endocytic uptake of FPR2 occurs independently of -arrestin, while Barbadin selectively augments FPR2-mediated neutrophil ROS production independently of receptor endocytosis.Given that Barbadin binds to AP2 and prevents the AP2/-arrestin interaction, our results indicate a role for AP2 in FPR2-mediated ROS release from human neutrophils. a large number of ligands belonging to different chemical classes [5][6][7]. Depending on the agonists examined, the signals generated by FPR2 mediate primarily pro-inflammatoryactivities, yet anti-inflammatory activities have also been described [8][9][10][11].…”

“…Based on the important roles of FPR2 in host defense and regulation of inflammation, this GPCR has been considered as a promising drug target for inflammatory conditions including cardiovascular diseases [12,13]. FPR2 transduces signaling primarily through heterotrimeric Gi/o proteins and the dissociated G subunits trigger activation of phospholipase C (PLC) associated with an increase in intracellular Ca 2+ [5,7]. For most GPCRs, recruitment of -arrestin desensitizes the agonist-occupied receptor at the plasma membrane, thereby terminating G protein-dependent signaling.…”

“…In addition, recruitment of -arrestin initiates receptor endocytosis/internalization and activation of non-canonical signaling [14]. The precise role of -arrestin in regulating FPR2 signaling and function is not known, but it is clear that some FPR2 agonists, but not all, are capable of promoting recruitment of -arrestin [5]. We have previously proposed that the dynamic transfer of agonist-occupied FPR2 from an active signaling state to a non-signaling state (i.e., receptor desensitization) is not directly associated with the ability of the receptoragonist complex to recruit -arrestin [9], but appears to involve receptor coupling to the actin 5 cytoskeleton [11,[15][16][17][18].…”