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Originally published online as doi:10.1189/jlb.1103552 on February 13, 2004

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(Journal of Leukocyte Biology. 2004;76:25-29.)
© 2004 by Society for Leukocyte Biology

Annexin 1 and the biology of the neutrophil

Mauro Perretti1 and Roderick John Flower

The William Harvey Research Institute, Bart’s and the London Queen Mary School of Medicine and Dentistry, Charterhouse Square, United Kingdom

1Correspondence: The William Harvey Research Institute, Bart’s and the London Queen Mary School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. E-mail: M.Perretti{at}qmul.ac.uk


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ABSTRACT
 
This overview will focus on one aspect of neutrophil biology, which is the selective activation of the annexin 1 system in relation to the process of cell extravasation. Besides the current view about the biochemistry of annexin 1 and annexin 1 receptor(s) up-regulation within the microenvironment of the adherent neutrophils, we will also comment on the final result achieved by activation of the system, which is inhibition of neutrophil recruitment. In view of the historical link between annexin 1 and glucocorticoids, the potential for the annexin 1 system in mediating at least some of the anti-inflammatory actions of these powerful drugs is also discussed.

Key Words: glucocorticoids • anti-inflammation • lipocortin • adhesion • trafficking • endothelium


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INTRODUCTION
 
Annexin 1 is one of several endogenous, anti-inflammatory mediators that operate in the body to ensure the transient profile of the inflammatory reaction, i.e., to prevent it from over-shooting, thereby causing damage to the host. We believe that a full effort in understanding how anti-inflammation is brought about can lead to its exploitation for innovative drug discovery. With regards to the annexin 1 system, the recent identification of the receptors involved in mediating the actions of this endogenous inhibitory mediator on the neutrophil represents a major step, close to taking full advantage for the development of novel annexino-mimetics.


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ANNEXIN 1 AND THE NEUTROPHIL
 
Human neutrophils contains in their cytosol large amounts (between 2% and 4%) of a single protein, annexin 1 [1 2 3 ]. Annexin 1 is a glucocorticoid-regulated member of a large superfamily (there are 13 mammalian annexins) of calcium and phospholipid-binding proteins, with a diverse distribution throughout different cell types [4 ]. However, why is there so much annexin 1 in human neutrophils, and what is its role in neutrophils biology? This overview will address these two points and provide a brief update on this exciting research area.

Within peripheral blood cells, annexin 1 is predominantly expressed by neutrophils, eosinophils, and monocytes, with lower amounts expressed in specific subsets of lymphocytes [5 , 6 ]. The protein is easily detectable in human neutrophil extracts by Western blotting [1 , 2 ], and following treatment of fixed and permeabilized cells with a specific antiannexin 1 monoclonal antibody, strong reactivity is seen by immunofluorescence or confocal microscopy [7 ]. The pattern of expression of the protein appears to be punctuate with patches of immunoreactivity seen throughout the cell. Subsequent electron microscopy and dual confocal analyses indicated that a good proportion of the protein was localized within a specific subset of neutrophil organelles [8 ]. Borregaard and Cowland [9 ] have recently classified vesicles and granules within human neutrophils and observed that their fusion with the plasma membrane varied as these cells interacted with the vascular endothelium. Our studies conducted with human resting neutrophils in vitro [8 ] and with rat neutrophils within an inflamed vascular bed in vivo [10 ] found that a majority (~50%) of intracellular annexin 1 colocalized with gelatinase, whereas a much smaller proportion was detected on the plasma membrane [10 ] (Fig. 1 ).



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  		Figure 1. Schematic steps of neutrophil activation sensitive to glucocorticoids and annexin 1. Blood neutrophils have high intracellular annexin 1 content, which is rapidly mobilized upon adhesion. It is unclear if cell activation would also alter annexin 1 localization/secretion. Integrated pharmacological and genetic approaches highlighted the inhibitory roles played by annexin 1 and glucocorticoids on either process. As an example, see refs. [11 12 13 14 15 16 ]. PMN, Polymorphonuclear neutrophil; ec, endothelial cell.

As with some other proteins [e.g., including interleukin 1 (IL-1) and galectin 1], annexin 1 lacks a signal peptide [17 ]; therefore, it cannot be exported through the classical secretory pathway. The specific localization of annexin 1 within the gelatinase granules solves the mystery of how this protein is externalized from the neutrophils, as these granules and their contents can be exported on the cell surface by a process of exocytosis, by analogy to the mechanisms described by Borregard and colleagues [9 , 18 ]. It is of interest that recent experiments indicate that vesicle association is also responsible for the secretion of IL-1 [19 ]. However, why does annexin 1 need to be secreted onto the neutrophil cell surface?


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ANNEXIN 1 EXTERNALIZATION
 
Pharmacological investigations have often opened the way for the characterization of the physiological and pathological roles of mediators, and we believe that this applies to the annexin 1 field. Originally identified as a mediator of glucocorticoid action [20 ], we observed more than a decade ago that human recombinant annexin 1 and its peptido mimetics were able toinhibit neutrophil recruitment in several models of acute inflammation [11 , 21 ]. In an inflamed microvascular bed (hamster cheek pouch), intravital microscopy analysis revealed that the potent, synthetic glucocorticoid dexamethasone inhibited leukocyte adhesion and emigration in an annexin 1-dependent manner [22 ] and that the inhibitory actions of the steroid were abrogated by passive immunization of animals with an antiannexin 1 antibody. This experiment suggested that the antigen, i.e., the annexin 1 protein, must be accessible to the antibody for it to blockade its functions. A similar result was obtained in other models of inflammation [23 , 24 ]. In parallel studies, we demonstrated that treatment with glucocorticoids increased annexin 1 content in circulating leucocytes in man [6 ] and rodents [25 ]. We now know that cytosolic annexin 1 is actively mobilized when the neutrophil adheres to the endothelium, thus providing an explanation for the efficacy of neutralizing antiannexin 1 antibodies (Fig. 2 ). As glucocorticoids augment annexin 1 content in cells, larger amounts of the protein will be externalized on the cell surface once the leukocyte adheres to the inflamed vascular endothelium. A survey of human donors indicated that between 50% and 70% of total annexin 1 is externalized onto the neutrophil surface upon adhesion to endothelial cell monolayers [27 ]. All the data from pharmacological studies with annexin 1 and its mimetics, as well as those with neutralizing antibodies, suggest a pivotal role for the protein in the control of neutrophil extravasation. It is noteworthy that within this specific microenvironment, other anti-inflammatory mediators can also operate including endothelial-derived nitric oxide [28 ] and leukocyte- or endothelial-derived adenosine [27 , 29 ].



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  		Figure 2. Altered annexin 1 expression in relation to the neutrophil extravasation process. Neutrophil adhesion to the postcapillary venule is the central step to export annexin 1 on the neutrophil plasma membrane. Besides externalization, a process of proteolysis also occurs within this microenvironment. Thus, electron microscopy analysis with specific antiannexin 1 antibodies indicated a predominance of intact annexin 1 (37-kDa species) on the cell surface of the adherent neutrophil (left panel) [10 ]. In contrast, extravasated neutrophils (right panel) displayed a majority of cleaved annexin 1 (33-kDa species), predominantly found intracellularly. Indications for de novo synthesis of the protein within the extravasated neutrophil were also gained [10 ]. It is interesting that endothelial cells (ec) in close vicinity to extravasated neutrophils also displayed higher annexin 1 content, predominantly 33-kDa species, possibly as a consequence of a transcellular transportation of the cleaved protein mediated by specific binding sites [26 ].


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MECHANISM OF ANNEXIN 1 ACTION
 
Annexin 1 and glucocorticoids have several largely inhibitory actions on the neutrophil [12 , 30 31 32 33 ] (Fig. 1) . In vivo, in the inflamed microcirculation model, intravenous (i.v.) injection of annexin 1 and peptido-mimetics provoked detachment of adherent neutrophils from inflamed postcapillary venules with rapid kinetics [34 ]. Neutrophils have high-affinity binding sites that recognize annexin 1 [35 , 36 ], and the detachment of adherent leukocytes from the inflamed endothelium might be the result of a receptor-mediated signaling process that interferes with the normal process of activation that leads to diapedesis. It is interesting that addition of annexin 1-derived N-terminal peptides to human neutrophils in suspension provoked transient changes in intracellular calcium. A seminal study by Walther et al. [37 ] focused the attention of annexin 1 researchers onto the formyl peptide receptor (FPR). Based on experiments using receptor antagonists in an in vitro assay of neutrophil locomotion [37 ], it was proposed that annexin 1-derived peptides activated neutrophils through occupation of FPR. We partially confirmed these observations but instead of an interaction with FPR itself, observed coimmunoprecipitation of endogenous annexin 1 with the related lipoxin A4 receptor (ALX) [38 ], cloned earlier [39 ]. ALX is also termed "FPR-like 1", as it has high homology (>70%) with the FPR family of G protein-coupled receptors [40 ]. However, in contrast to the experiments of Walther et al. [37 ], annexin 1 interaction with ALX was substantiated by binding data, which demonstrated direct competition among lipoxin A4, annexin 1, and its peptides [38 ], as well as with another agonist at this receptor, serum amyloid protein A [41 ]. The functional interaction between annexin 1 and ALX was also supported by in vivo experiments in which the annexin 1 mimetic peptide acetyl-2-26 (Ac2-26) was able to synergize with a stable lipoxin analog in inhibiting neutrophil recruitment [38 ].


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DO DIFFERENT RECEPTOR SUBTYPES COORDINATE DIFFERENT ASPECTS OF THE ANTI-INFLAMMATORY RESPONSE?
 
A detailed analysis of the antineutrophil actions of annexin 1 in mice deficient in the murine FPR ortholog gene suggests distinct roles for each receptor. The antimigratory effect of peptide Ac2-26 in peritoneal inflammation induced by zymosan A was absent in FPR null mice [42 ], but the inhibitory action of the full-length annexin 1 was largely preserved. In a model of ischaemia reperfusion-induced leukocyte interaction with a mesentery vascular wall, the antiadhesive effect of the annexin 1-derived peptide was only partially (~50%) affected by FPR gene deletion [43 ], whereas its inhibition of plasma protein extravasation was fully preserved in FPR-deficient mice [43 ]. It is important that the ability to promote detachment of adherent leukocytes from the mesenteric venules, as initially reported by us [34 ], was shared by peptide Ac2-26 and a stable lipoxin A4 analog and that they had a similar efficacy and kinetics. However, i.v. injection of the chemokine KC or formyl-Met-Leu-Phe (fMLP) itself (at doses known to provoke neutrophil activation and recruitment), did not provoke cell detachment and actually increased leukocyte adhesion (ref. [43 ] and unpublished data).

Bulky butoxycarbonyl derivatives of short peptides have been characterized as FPR antagonists [44 ] and were used by the Muenster group to highlight a role for this receptor in the inhibitory actions of annexin 1-derived peptides [37 , 45 ]. However, at least one of these antagonists, butoxycarbonyl-Phe-Leu-Phe-Leu-Phe (Boc2) blocked serum amyloid A-induced activation of ALX [38 ]. The same was true in the murine-inflammatory models. Activation of FPR-deficient neutrophils by high concentrations of fMLP, monitored as up-regulation of cell-surface CD11b expression, was also blocked by the Boc2 compound, clearly indicating its ability to interact with receptors other than FPR [43 ]. The same is very likely to occur in the rat system [46 ].

Characterization of the receptor system responsible for anti-inflammatory (antineutrophil) actions of annexin 1 and its peptido-mimetics indicates a degree of tissue specificity and a complex scenario is emerging with respect to the role of the annexin 1 system within the microenvironment of an adherent leukocyte. Protein export onto the cell surface is followed by interaction with the receptor, post-receptor signaling events such as transient calcium fluxes [37 , 38 , 47 ], and ultimately, a controlled leukocyte activation leading to the detachment phenomenon itself. We often refer to this as an autocrine action of annexin 1 [27 ]; however, we cannot exclude the possibility that the protein might also act in a paracrine manner. It is interesting that specific annexin 1-binding sites on endothelial cells have also been reported [26 ]. Our own electron microscopy studies suggested the existence of a complex neutrophil/endothelium interaction leading to annexin 1 mobilization from the adherent neutrophil and internalization by endothelial cells [10 ]. Figure 2 highlights this process.


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POST-TRANSLATIONAL CONTROL OF ANNEXIN 1 DISPOSITION IN THE NEUTROPHIL
 
It is likely that the annexin 1 system in the neutrophil can be finely regulated by post-translational mechanisms. The annexin 1 N-terminal region, which is unique to this member of the family [4 ], contains several putative phosphorylation sites. For instance, epidermal growth factor receptor activation leads to annexin 1 phosphorylation on tyrosine 21 [48 ]. More recently, protein kinase C (PKC)-dependent serine/threonine phosphorylation has been reported in a pituitary cell line [49 ], and this was essential to externalization of the protein. It is interesting that PKC-dependent phosphorylation of annexin 1 has already been reported in neutrophils [50 ]. It is likely that the fate of annexin 1 within human neutrophils might also be determined by phosphorylation in a stimulus-specific manner—this representing a subtle mechanism of control over the location and activity of the protein.

Neutrophil adhesion to the endothelial monolayer provokes annexin 1 release into the medium [7 ], but annexin 1 secreted in this way is predominantly N-terminus-cleaved. Recent unpublished results indicate the existence of a phenylmethylsulfonyl fluoride-sensitive enzymatic activity responsible for annexin 1 cleavage. However, a metalloprotease has also been proposed to cleave the first seven amino acid of the annexin 1 N-terminus [51 ]. Whereas this aspect warrants further analysis, it is already conceivable that annexin 1 cleavage might be of clinical relevance. In fact, bronchoalveolar lavage fluids of patients suffering from cystic fibrosis and other lung pathologies display a marked degree of annexin 1 proteolysis [52 , 53 ]. These two studies proposed a role for elastase as the putative proteolytic annexin 1-cleavage enzyme. In line with the data just discussed, annexin 1 (intact and cleaved) is often recovered from inflammatory exudates and inflamed tissues and corresponds to the peak of neutrophilia [54 , 55 ]. Second, it has yet to be determined whether annexin 1 cleavage is primarily a catabolic pathway or whether by liberating the N-terminal pharmacophore, it is actually part of an activating phenomenon.


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LESSONS FROM ANNEXIN 1-DEFICIENT MICE
 
The fundamental role played by this protein has recently been corroborated by studies in mice knockout for its gene [56 ]. Whereas these animals bred normally, they displayed two major features related to experimental inflammation: augmented and/or prolonged inflammatory reaction and partial resistance to the anti-inflammatory effect of dexamethasone. Both aspects were initially studied using acute models of inflammation (paw edema and zymosan peritonitis), however have subsequently been determined in a chronic model of joint inflammation [57 ]. Initial characterization of neutrophils deficient in annexin 1 indicated a higher susceptibility to activation [56 ], although more systematic investigations are yet to come. Analysis of the inflamed microcirculation of annexin 1-deficient mice indicates a higher susceptibility for adherent leukocytes to enter into diapedesis across cremaster venules in response to platelet-activating factor superfusion (Bristi E. Chatterjee, R. J. F., M. P., unpublished data).


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CONCLUSION
 
A decade of research into the pharmacological effects of human recombinant annexin 1 and its N-terminal-derived peptides in models of neutrophil recruitment has led to the discovery of a complex biochemical system operating within the microenvironment of an adherent neutrophil. In terms of its role in pathophysiology, the salient points are: The protein is highly expressed in the neutrophil cytosol; it can be rapidly mobilized to the cell surface when the neutrophil adheres onto endothelium; here, it interacts with receptors that belong to a specific family of "chemotactic" G protein-coupled receptors, most likely ALX; although it is not known which molecular mechanisms operate downstream from receptor activation in this context, the end-point is controlled neutrophil activation and detachment; and this regulatory action of annexin 1 is probably terminated through a specific, proteolytic event. This scenario is supported by a wealth of experimental data; however, it is clear that more research effort needs to be spent on specific aspects of the annexin 1 system in neutrophil biology.


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ACKNOWLEDGEMENTS
 
The Arthritis Research Campaign UK (Fellowship P0583) and the Wellcome Trust UK (Program Grant 069234/Z/02/Z) predominantly funded the research activities on annexin 1 in the authors’ laboratory.

Received November 11, 2003; accepted December 30, 2003.


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