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Microvasculature Receptor and Operative in the Inflamed 4 Formyl Evidence for an Anti-Inflammatory Loop Centered on Polymorphonuclear Leukocyte Formyl Peptide Receptor 2/Lipoxin A4 Receptor and Operative in the Inflamed This information is current as Microvasculature of September 28, 2021. Vincenzo Brancaleone, Jesmond Dalli, Stefania Bena, Roderick J. Flower, Giuseppe Cirino and Mauro Perretti J Immunol 2011; 186:4905-4914; Prepublished online 11 March 2011; Downloaded from doi: 10.4049/jimmunol.1003145 http://www.jimmunol.org/content/186/8/4905 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2011/03/11/jimmunol.100314 Material 5.DC1 References This article cites 70 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/186/8/4905.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Evidence for an Anti-Inflammatory Loop Centered on Polymorphonuclear Leukocyte Formyl Peptide Receptor 2/Lipoxin A4 Receptor and Operative in the Inflamed Microvasculature Vincenzo Brancaleone,*,† Jesmond Dalli,* Stefania Bena,* Roderick J. Flower,* Giuseppe Cirino,† and Mauro Perretti* 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 A4 (LXA4) and annexin A1 (AnxA1) because these two very different mediators converge on a single receptor, formyl Downloaded from peptide receptor type 2 (FPR2/ALX). Addition of LXA4 to human polymorphonuclear leukocytes (PMNs) provoked a concentra- tion- 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 LXA4 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 http://www.jimmunol.org/ intermediate phosphorylation step. Intravital microscopy investigations of the inflamed mesenteric microvasculature of wild-type 2/2 and AnxA1 mice revealed that LXA4 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- 2/2 pouches, inflamed with IL-1b, was significantly attenuated by LXA4 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. The Journal of Immunology, 2011, 186: 4905–4914. by guest on September 28, 2021 t is now appreciated that the process of acute inflammation Lipoxin A4 (LXA4) (2) and annexin A1 (AnxA1) are two ef- relies on the active involvement of a series of proresolving fectors of endogenous anti-inflammation (4) that are able to halt I mediators that ensure temporal and spatial containment of the leukocyte migration (5, 6) and promote macrophage phagocytosis host reaction (1). Therefore, a proinflammatory phase is followed by of infective agents as well as apoptotic leukocytes (7–9). In 2002, an anti-inflammatory and proresolving phase in line with “the we reported that this short-lived lipid, produced by transcellular beginning programs the end” concept recently put forward (2). synthesis and cooperation between lipoxygenases (10), and the However, whereas it is well accepted that proinflammatory media- glucocorticoid-regulated protein both converged on a specific re- tors (e.g., cytokines, chemokines, autacoids) often act in concert in ceptor target (11), the formyl peptide receptor type 2 [FPR2/ALX; a network-like fashion (3), the significance of such networks to currently used to identify the human receptor (12)]. inflammatory resolution has been poorly appreciated, and specific LXA4 and AnxA1 are very different not only chemically but mediators and pathways have often been investigated in isolation. also with respect to their biosynthesis (produced on demand or stored in cell sources) and metabolic fate; we questioned *William Harvey Research Institute, Barts and The London School of Medicine, whether a functional link existed between them that justified Queen Mary University of London, London EC1M 6BQ, United Kingdom; and a single receptor as the main transducer for their essentially † Dipartimento di Farmacologia Sperimentale, Universita´ degli studi di Napoli, similar proresolving properties. In addition, comparing the time 80129 Naples, Italy course of generation of these two mediators during acute in- Received for publication September 22, 2010. Accepted for publication February 13, 2011. flammation in mice and men reveals distinct windows for syn- thesis and secretion, with exudate LXA concentrations peaking This work was supported by the Wellcome Trust (Programme 086867/Z/08) and 4 forms part of the research themes contributing to the translational research portfolio at a much earlier time point than AnxA1 concentrations. In of Barts and the London Cardiovascular Biomedical Research Unit, which is sup- murine air-pouches, inflamed with the TLR2 agonist zymosan, ported and funded by the National Institutes of Health Research. LXA4 peaks at 4 h, whereas exudate AnxA1 expression is Address correspondence and reprint requests to Prof. Mauro Perretti, William Harvey highest at 24 h, coinciding with the peak of polymorphonuclear Research Institute, Barts and The London Medical School, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail address: [email protected] leukocyte (PMN) influx (11). The same holds true in the zy- The online version of this article contains supplemental material. mosan peritonitis model (13, 14). Furthermore, 15-epi-lipoxin Abbreviations used in this article: AF2, antiflammin 2; AnxA1, annexin A1; CsH, induced by low-dose aspirin treatment inhibits leukocyte re- cyclosporin H; CTR, control; FPR2/ALX, formyl peptide receptor 2/lipoxin A4 re- cruitment in a human skin blister model of acute inflammation ceptor; LXA4, lipoxin A4; MFI, median fluorescence intensity; PMN, polymorpho- (15); in the same model, a delay in the onset of the inflammatory nuclear leukocyte; WRW , peptide WRWWWW. 4 response, seen in ∼40% of individuals, is associated with ab- Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 normal production of 15-epi-lipoxin (16). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1003145 4906 ANNEXIN A1 IS MOBILIZED BY FPR2/ALX AGONISTS AnxA1 is very abundant in human PMNs, representing between lysis buffer was used, and the cells were sheared through a 25-gauge 2 and 4% of total intracellular proteins (17). In resting PMNs, needle 10 times. Lysates were subsequently centrifuged for 2 min at 3003 3 a proportion (∼60%) of intracellular AnxA1 is localized in gela- g, and supernatants centrifuged again for 45 min at 800 g. The resulting supernatant (cytosolic fraction) was collected and the remaining pellet tinase and azurophilic granules (18, 19), with the remaining being resuspended in 20 mM Tris-HCl, 1% Triton X-100, pH 7.5 (100 ml), for 15 cytosolic in location. PMN adhesion to endothelial cell monolayers min (membrane fraction). Membrane-bound AnxA1 was recovered by provokes a rapid mobilization of AnxA1 onto the cell surface washing pelleted cells twice with 50 ml 1 mM EDTA. (20), where this agonist could encounter its receptor to activate Western blot analysis juxtacrine and/or autocrine signals (6), thus curtailing the extent of neutrophil trafficking (21). Nonetheless, the cytosolic nongra- Samples boiled in 63 Laemmli buffer were subjected to standard SDS- nular pool of the protein can also be mobilized, as, for instance, PAGE (12%) and electrophoretically blotted onto polyvinylidene difluor- ide membranes (PVDF; Millipore, Watford, U.K.). Membranes were in- in response to drug application (22–24), and the latter process cubated with the mouse mAbs anti-human AnxA1 [clone 1B; dilution, 27 entails a phosphorylation step at Ser (and possibly other resi- 1:1,000 (37)] and anti-human actin (1:10,000; Sigma-Aldrich) in TBST dues), which seems to be a prerequisite for secretion of the protein and 5% (w/v) nonfat dry milk overnight at 4˚C. Membranes were washed onto the cell surface (25). for 30 min with TBST, with the solution being changed at 10-min inter- Antiflammin 2 (AF2) is a nonapeptide corresponding
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