Pituitary Adenylate Cyclase-Activating Polypeptide 27 Is a Functional Ligand for Formyl Peptide Receptor-Like 1

Abstract

Although the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in the regulation of several immune responses, its target receptors and signaling mechanisms have yet to be fully elucidated in immune cells. In this study, we found that PACAP27, but not PACAP38, specifically stimulated intracellular calcium mobilization and ERK phosphorylation in human neutrophils. Moreover, formyl peptide receptor-like 1 (FPRL1) was identified as a PACAP27 receptor, and PACAP27 was found to selectively stimulate intracellular calcium increase in FPRL1-transfected rat basophile leukocytes-2H3 cell lines. In addition, PACAP27-induced calcium increase and ERK phosphorylation were specifically inhibited by an FPRL1 antagonist, Trp-Arg-Trp-Trp-Trp-Trp (WRW4), thus supporting the notion that PACAP27 acts on FPRL1. In terms of the functional role of PACAP27, we found that the peptide stimulated CD11b surface up-regulation and neutrophil chemotactic migration, and that these responses were completely inhibited by WRW4. The interaction between PACAP27 and FPRL1 was analyzed further using truncated PACAPs and chimeric PACAPs using vasoactive intestinal peptide, and the C-terminal region of PACAP27 was found to perform a vital function in the activation of FPRL1. Taken together, our study suggests that PACAP27 activates phagocytes via FPRL1 activation, and that this results in proinflammatory behavior, involving chemotaxis and the up-regulation of CD11b.

Vasoactive intestinal peptide dampens formyl-peptide-induced ROS production and inflammation by targeting a MAPK-p47phox phosphorylation pathway in monocytes

“…The PACAP-27/FPR1 activation is responsible for the associated induced ROS production, as well as chemotactic migration CD11b surface upregulation, and cytokine production. 27 In our study, we found that either PACAP-38 or VIP inhibited fMLF-induced ROS response in whole blood in favor of a predominant VPAC1 interaction in line with VIP/VPAC1 major control of immunological answer in animal studies. 28 .…”

“…However, PACAP-27, unlike the predominant extended peptide PACAP-38, stimulates cytoplasmic calcium mobilization and phosphorylation ERK in both human monocytes and neutrophils and promote ROS production by itself. 26,27 The proposed explanation is that PACAP-27 is a functional ligand of the high-affinity receptor FPR1 of fMLF present in phagocytes. The PACAP-27/FPR1 activation is responsible for the associated induced ROS production, as well as chemotactic migration CD11b surface upregulation, and cytokine production.…”

VIP differentially activates β2 integrins, CR1, and matrix metalloproteinase-9 in human monocytes through cAMP/PKA, EPAC, and PI-3K signaling pathways via VIP receptor type 1 and FPRL1

“…Recently, it was reported that in neutrophils, the proinflammatory effects of PACAP were mediated by VPAC1 and FPRL1, the low-affinity FPR receptor [43]; in this study, VIP was reported to have no effect on calcium or ERK phosphorylation. In contrast, we found that in monocytes, VIP increases cAMP, phosphorylates Akt, ERK, and p38, and up-regulates CD11b, CD35 membrane expression, and MMP-9 secretion, indicating that monocytes are sensitive to VIP.…”

Novel function of recombinant pituitary adenylate cyclase-activating polypeptide as stimulator of innate immunity in African catfish (Clarias gariepinus) fry

“…During recent years, the role of PACAP in immunoregulation has been partially elucidated in mammals [11][12][13][14] demonstrating that PACAP modulates both innate and adaptive immunity. In general, only preliminary studies on PRP functions have been done in mammals [15,16], therefore studies on PRP functions over immunity are still missing.…”