title: Evidence for an anti-inflammatory loop centered on polymorphonuclear leukocyte formyl peptide receptor 2/lipoxin A4 receptor and operative in the inflamed microvasculature.
abstract: The importance of proresolving mediators in the overall context of the resolution of acute inflammation is well recognized, although little is known about whether these anti-inflammatory and proresolving molecules act in concert. In this article, we focused on lipoxin A(4) (LXA(4)) and annexin A1 (AnxA1) because these two very different mediators converge on a single receptor, formyl peptide receptor type 2 (FPR2/ALX). Addition of LXA(4) to human polymorphonuclear leukocytes (PMNs) provoked a concentration- and time-dependent mobilization of AnxA1 onto the plasma membrane, as determined by Western blotting and flow cytometry analyses. This property was shared by another FPR2/ALX agonist, antiflammin-2, and partly by fMLF or peptide Ac2-26 (an AnxA1 derivative that can activate all three members of the human FPR family). An FPR2/ALX antagonist blocked AnxA1 mobilization activated by LXA(4) and antiflammin-2. Analysis of PMN degranulation patterns and phospho-AnxA1 status suggested a model in which the two FPR2/ALX agonists mobilize the cytosolic (and not the granular) pool of AnxA1 through an intermediate phosphorylation step. Intravital microscopy investigations of the inflamed mesenteric microvasculature of wild-type and AnxA1(-/-) mice revealed that LXA(4) provoked leukocyte detachment from the postcapillary venule endothelium in the former (>50% within 10 min; p < 0.05), but not the latter genotype (∼15%; NS). Furthermore, recruitment of Gr1(+) cells into dorsal air-pouches, inflamed with IL-1β, was significantly attenuated by LXA(4) in wild-type, but not AnxA1(-/-), mice. Collectively, these data prompt us to propose the existence of an endogenous network in anti-inflammation centered on PMN AnxA1 and activated by selective FPR2/ALX agonists.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Brancaleone
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.forename: Stefania
authors.initials: S
authors.lastname: Bena
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Flower
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D044045:Lipoxins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D044042:Receptors, Formyl Peptide / Q000276:immunology* / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D017305:Annexin A1; D000894:Anti-Inflammatory Agents, Non-Steroidal; C105101:FPR2 protein, human; D018836:Inflammation Mediators; D044045:Lipoxins; D009842:Oligopeptides; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C040527:lipoxin A4; C064647:antiflammin P2