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Anti-adhesive proteins and resolution of neutrophil-mediated inflammation
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Please cite this article as: Pliyev, B.K., Anti-adhesive proteins and resolution of neutrophil-mediated inflammation, Immunobiology (2013), http://dx.doi.org/10.1016/j.imbio.2013.03.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
*Manuscript
Anti-adhesive proteins and resolution of neutrophil-mediated inflammation Boris K. Pliyev1,* 1
, Institute of Immunology, Kashirskoye Shosse 24-2, Moscow 115478, Russia,
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*, corresponding author:
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Boris K. Pliyev, PhD
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Institute of Immunology Kashirskoye Shosse 24-2
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Moscow 115478, Russia
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Tel.: 7-499-617-7649
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Fax: 7-499-617-1027
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E-mail: [email protected]
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Abstract The onset of inflammatory response is associated with neutrophil recruitment into infected or injured tissues, whereas the resolution of inflammation, on the contrary, requires blockade of further recruitment and clearance of the recruited cells. Adhesion of circulating
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neutrophils to the endothelium represents a crucial step in their recruitment into the inflamed tissues. Previous studies have identified a number of proteins which can interfere with
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neutrophil-endothelial adhesive interactions and act as natural inhibitors of the leukocyte egress
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from the circulation. Essentially, these proteins are up-regulated in inflammation and, therefore, have potential pro-resolving activity. Knockout animals deficient in the anti-adhesive proteins
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demonstrated increased magnitude and duration of acute inflammation indicating that the proteins play a non-redundant role in dampening the inflammatory response. This paper is a
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review of the experimental data supporting the hypothesis that the up-regulation of the anti-
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resolution of inflammation.
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adhesive proteins may represent an anti-inflammatory mechanism that contributes to the
Key words: inflammation, resolution, neutrophils, anti-adhesive proteins
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1. Introduction A hallmark of inflammation is the recruitment of leukocytes to infected or injured tissues. Neutrophils are the first cells that arrive at sites of infection or injury and play a key role in the inflammatory response (Mantovani et al., 2011). Acute inflammatory response is a finite self-
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resolving process and is accompanied by a transient neutrophil recruitment, whereas in nonresolving chronic inflammation, the recruitment may continue over months or years. Restoration
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of tissue neutrophil homeostasis is considered to be a critical event in the resolution of
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inflammation (Bratton and Henson, 2011). Consequently, the resolution phase is defined as the interval from maximal neutrophilic infiltration to the point when they are lost from the tissue
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(Serhan et al., 2007). It is now accepted that the resolution process is active, rather than passive, and is controlled by a number of mechanisms which are switched on in the course of resolving
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inflammation. The established pro-resolving mechanisms include tissue neutrophil apoptosis followed by phagocytosis of the apoptotic cells by macrophages, retrograde neutrophil migration
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from the inflamed area and generation of lipid mediators which block the ongoing neutrophil recruitment. Results from previous studies raise the hypothesis that the pro-resolving
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mechanisms may also involve inflammation-triggered up-regulation of proteins that block and/or disrupt neutrophil-endothelial cell interactions and thereby prevent neutrophil recruitment. In the following sections, I will briefly overview the established mechanisms which restore tissue
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neutrophil homeostasis in resolving inflammation and will consider the experimental data supporting the hypothesis that the up-regulation of the anti-adhesive proteins may represent an essential pro-resolving mechanism. 2. Restoration of tissue neutrophil homeostasis in resolving inflammation Regulated apoptosis of neutrophils in an inflamed tissue followed by their phagocytosis (efferocytosis) by recruited monocyte-derived macrophages is considered to be one of the major mechanisms which are responsible for tissue neutrophil clearance in resolving inflammation
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(Bratton and Henson, 2011). In addition, neutrophils have been shown to traffic bidirectionally between sites of inflammation and the vasculature and the retrograde neutrophil migration to the vasculature has been suggested to be an alternative mechanism by which inflammation is resolved (Hughes et al., 1997; Mathias et al., 2006). Moreover, neutrophil migration across the epithelium into luminal spaces may also contribute to the cell clearance from the tissue. For
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example, neutrophil egress into airspaces is considered as a possible mechanism that resolves
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airway inflammation (Uller et al., 2006). Interestingly, neutrophil emigration from the inflamed tissue can exceed neutrophil clearance by apoptosis (Hughes et al., 1997). Thus, neutrophil
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egress from the inflamed tissue can complement regulated neutrophil apoptosis to restore tissue
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neutrophil homeostasis and to resolve inflammation (Fig. 1A).
To quench tissue neutrophilia in the inflamed area, the elimination/efflux of the recruited
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neutrophils is not enough. The ongoing neutrophil infiltration into the tissue must also be halted. The mechanisms that negatively regulate neutrophil recruitment in resolving inflammation are
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not completely understood. The cessation of neutrophil influx can be achieved by mechanisms that normalize chemokine gradients which cause neutrophil recruitment and/or mechanisms that
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actively prevent neutrophil migration into inflamed tissues. The former depend on reversion of chemoattractant-producing parenchymal/stromal cells that hosted the inflammatory event back to a non-inflammatory phenotype (Filer et al., 2006). For example, macrophages ingesting
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apoptotic neutrophils produce anti-inflammatory mediators, such as IL-10 and TGF-, which can restore non-inflammatory stromal microenvironment (Fox et al., 2010). However, the mechanisms exist that actively counteract neutrophil recruitment in resolving inflammation. An established mechanism that actively suppresses neutrophil recruitment in the course of the inflammatory response is generation of specialized anti-inflammatory lipid mediators which represent local stop signals preventing further or excessive neutrophil entry into tissue (Fig.1A). Endogenous lipid mediators with anti-inflammatory and pro-resolving activity include
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lipoxins, which are biosynthesized from arachidonic acid, and omega-3 polyunsaturated fatty acid-derived resolvins, protectins and maresins (Norling and Serhan, 2010). The antiinflammatory lipid mediators have been shown to inhibit neutrophil transendothelial migration in vitro and reduce neutrophil infiltration into inflamed tissues in models of acute inflammation in vivo, thereby dampening the inflammatory response (Serhan et al., 2006; Serhan, 2007; Sun et
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al., 2007; Serhan et al., 2012). Besides the generation of the anti-inflammatory lipids, other
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mechanisms may suppress neutrophil recruitment in resolving inflammation. One of such mechanisms can be up-regulation of anti-adhesive proteins which disrupt neutrophil-endothelial
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adhesive interactions and thus prevent neutrophil egress from the circulation (Fig. 1B).
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3. Anti-adhesive proteins as negative regulators of neutrophil recruitment in resolving inflammation
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Early in the inflammatory response, cytokines and chemoattractants produced in an
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inflamed tissue activate the microvascular endothelium resulting in induction of cell adhesion molecules within the local microcirculation. The up-regulated cell adhesion molecules mediate
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chemoattractant-induced neutrophil adhesion to the inflamed endothelium and subsequent transendothelial migration. The molecular mechanisms involved in neutrophil-endothelial cell adhesive interactions have been extensively reviewed elsewhere (Ley et al., 2007). Briefly,
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sequential initial steps of neutrophil-endothelial interactions are tethering, rolling, activation and firm adhesion (arrest). Neutrophil tethering and rolling are mediated by selectins; L-selectin is expressed constitutively on leukocytes, whereas activated endothelial cells express E- and Pselectins. The selectins interact with their counter-receptors on leukocytes and endothelial cells (Rosen, 2004; Zarbock et al., 2011). Subsequent firm adhesion of neutrophils to the endothelium is predominantly mediated by β2 integrins LFA-1 (L2) and Mac-1 (M2) (Smith et al., 1989; Ley et al., 2007). Neutrophil activation by chemoattractants and cytokines produced by the inflamed tissue induces conformational changes in β2 integrins necessary for enhanced ligand
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recognition. The activated LFA-1 and Mac-1 firmly bind to their major counter-receptor intercellular cell adhesion molecule-1 (ICAM-1) on endothelial cells. Results of numerous studies indicate that, besides the up-regulation of the cell adhesion molecules which mediate neutrophil extravasation, inflammation also triggers up-regulation of
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proteins which can inhibit neutrophil-endothelial adhesive interactions and, thus, act as negative regulators of the leukocyte egress from the circulation (Table 1). Knockout mice deficient in the
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anti-adhesive proteins demonstrated increased magnitude and duration of acute inflammation,
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whereas overexpression or intravenous injection of the proteins significantly attenuated neutrophil recruitment and quenched the inflammatory response in experimental models of
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inflammation. These data indicate that the anti-adhesive proteins play an important role in dampening the inflammatory response in vivo. Therefore, the up-regulation of the anti-adhesive
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proteins in inflammation can potentially be considered as a mechanism that complements the induction of pro-resolving lipids to prevent neutrophil recruitment in resolving inflammation
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(Fig. 1B). Of note, many of the proteins listed in Table 1 belong to classical positive acute phase reactants which expression and release into the circulation are up-regulated in response to
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bacterial infections, wounding and other unspecific inflammatory stimuli (Gabay and Kushner, 1999). Below, I will review the anti-adhesive proteins and the experimental data that demonstrate their essential role in negative regulation of neutrophil recruitment in resolving
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inflammation.
3.1. Pentraxin 3 (PTX3) Pentraxin 3 (PTX3) is an acute phase protein secreted by various cells including leukocytes and endothelial cells. Its plasma levels in humans are very low in normal conditions (2 ng/ml) but increase rapidly (peak at 6-8 hours) and dramatically (up to 200-800 ng/ml) during sepsis, endotoxic shock and other inflammatory and infectious conditions, correlating with the severity of the disease (Mantovani et al., 2008). PTX3 has been shown to bind to P-
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selectin and inhibits P-selectin-dependent neutrophil rolling (Deban et al., 2010). Consistent with its anti-adhesive property, the protein exerted anti-inflammatory effects in various experimental models of acute inflammation. For example, administration of exogenous recombinant PTX3 to mice inhibited acid-induced recruitment of neutrophils to the lungs and chemokine-induced entry of neutrophils into the pleural cavity to the same extent as antibody blockade or genetic
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deficiency in P-selectin (Deban et al., 2010). Moreover, PTX3-deficient mice have been shown
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to be more susceptible to ischemia-reperfusion injury and LPS-induced acute lung injury, and the increased inflammation-induced tissue injury in PTX3-deficient mice was associated with the
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increased neutrophil recruitment in the inflamed tissues (Salio et al., 2008; Han et al., 2011).
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3.2. C-reactive protein (CRP)
The pentraxin C-reactive protein (CRP) is the most characteristic acute phase protein in
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humans. In healthy individuals, plasma concentration of CRP is less than 1 µg/ml, but it can
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rapidly (within hours) increase up to 1,000-fold in response to an inflammatory event peaking at 24 - 48 hours after the induction of inflammation (Marnell et al., 2005). The magnitude of the
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CRP response in humans is related to the severity of inflammation or the extent of tissue injury. CRP has been shown to inhibit neutrophil recruitment in inflammation. For example, in experimental models of alveolitis, transgenic mice with high plasma levels of CRP exhibited
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diminished neutrophil infiltration compared with normal mice (Heuertz et al., 1993). In the same model of inflammation, intravenous administration of recombinant CRP significantly reduced neutrophil recruitment in rabbits (Heuertz et al., 1994). In in vitro experiments, CRP markedly attenuated neutrophil adhesion to endothelial cells and induced shedding of L-selectin from neutrophil plasma membrane without inducing generalized neutrophil activation (Zouki et al., 1997; El Kebir et al., 2011). The anti-adhesive effect of CRP was prevented by inhibition of Lselectin shedding indicating that CRP inhibits neutrophil-endothelial interaction by decreasing the surface expression of L-selectin (Zouki et al., 1997).
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3.3. 1-Acid glycoprotein (AGP) 1-Acid glycoprotein (AGP) is one of the major positive acute phase reactants. In humans, the normal average plasma levels of AGP are 0.5-1 mg/ml, whereas in disease it can reach 3 mg/ml (Ceciliani and Pocacqua, 2007). The protein is not only up-regulated during
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inflammation, but also undergoes structural modifications of its oligosaccharide moiety. Strikingly, acute inflammation induces a strong increase in AGP molecules bearing sialyl Lewisx
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(sLex), the minimal carbohydrate epitope recognized by all three selectins. The sLex-bearing
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AGP glycoforms persist at a high level throughout the inflammatory period suggesting that they may competitively interfere with leukocyte rolling in inflammation (De Graaf et al., 1993).
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Indeed, these AGP glycoforms have been shown to inhibit the adhesion of sLex-expressing cells to immobilized E-selectin (Jørgensen et al., 1998). AGP, when administered intravenously,
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inhibited carrageenan-induced neutrophil recruitment into the rat peritoneal cavity (Mestriner et al., 2007). Intravital microscopy demonstrated that AGP inhibited rolling and adhesion of
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leukocytes in the mesenteric microcirculation. The inhibitory effect of AGP was blocked by aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS), and was not observed in
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iNOS-deficient mice suggesting that AGP affects leukocyte recruitment via NO-dependent mechanism (Mestriner et al., 2007).
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3.4. Galectin-1
Galectin-1 is a mammalian lectin expressed by a variety of cell types and is up-regulated
in inflammatory conditions (Baum et al., 1995; Iqbal et al., 2011; Stancic et al., 2011). The protein inhibits neutrophil-endothelial adhesive interactions and acts as an endogenous regulator of neutrophil trafficking in inflammatory response. For example, in a model of IL-1-induced peritonitis in mice, exogenous galectin-1 reduced leukocyte adhesion and emigration in the mesenteric microcirculation (La et al., 2003). In another study, IL-1-induced neutrophil adhesion and emigration were increased in the cremasteric circulation of galectin-1-deficient
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mice compared with wild-type animals (Cooper et al., 2008). Galectin-1 has been shown to inhibit chemoattractant-induced neutrophil activation suggesting that this may represent a mechanism of the anti-adhesive effect of the protein (Cooper et al., 2008). Human neutrophils express little if any detectable galectin-1, but bind the exogenous protein. Preincubation of neutrophils with recombinant galectin-1 significantly decreased the extent of rolling and
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adhesion of the cells on activated endothelium (Cooper et al., 2008). Endothelial cells, in
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contrast to neutrophils, express high amounts of galectin-1 and its expression is up-regulated by proinflammatory cytokines (Baum et al., 1995; La et al., 2003). Small interfering RNA-mediated
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knockdown of galectin-1 in endothelial cells resulted in an increase in neutrophil rolling and adhesion on activated endothelium, suggesting that endogenous galectin-1 presented by the
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endothelium acts as negative regulator of neutrophil adhesion (Cooper et al., 2008).
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3.5. Annexin 1
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Annexin 1 is constitutively expressed by many cell types and is up-regulated in response to inflammatory stimuli (Solito et al., 1998; Yang et al., 1999; Särndahl et al., 2010). The effects
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of annexin 1 on neutrophil trafficking were tested in a variety of experimental animal models of inflammation: the administration of the recombinant protein exerted an anti-inflammatory effect and dampened neutrophil recruitment, whereas annexin 1-deficient mice displayed a higher
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degree of neutrophil infiltration compared with wild-type mice (Lim et al., 1998; La et al., 2001; Chatterjee et al., 2005). Exogenous annexin 1 has been shown to inhibit neutrophil firm adhesion to the endothelium both in vitro and in vivo (Lim et al., 1998; Hayhoe et al., 2006). Neutrophils contain extensive intracellular pool of annexin 1 which is localized predominantly in gelatinase granules and is mobilized onto the cell surface when neutrophils adhere to the endothelium (Perretti and Flower; 2004). The mobilized protein exerts the anti-adhesive effect in an autocrine/paracrine fashion via formyl-peptide receptor-like 1 (FPRL1), a leukocyte receptor for annexin 1 (Hayhoe et al., 2006). The protein expression in circulating neutrophils has been reported to be significantly increased in inflammation, suggesting that, in resolving Page 9 of 28
inflammation, neutrophils can negatively regulate their own recruitment by producing larger amounts of annexin 1 upon interaction with the endothelium (Särndahl et al., 2010). 3.6. Soluble adhesion molecules (soluble selectins and ICAM-1) The cell adhesion molecules involved in neutrophil-endothelial interactions, such as
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selectins and ICAM-1, can be shed from the cell surface and the shedding is increased in various inflammatory conditions elevating the plasma levels of the soluble forms (Giddings; 2005). The
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soluble adhesion molecules can competitively inhibit the adhesive interactions of their
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membrane counterparts, thus interfering with neutrophil-endothelial adhesive interactions. Indeed, soluble selectins and ICAM-1 have been identified as major factors responsible for the
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inhibitory effect of normal plasma on neutrophil adhesion to the endothelium in vitro (Ohno et al., 1997). Wang et al. generated a transgenic mouse model overexpressing the extracellular
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domain of mouse ICAM-1 in the liver (Wang et al., 2005). Compared with wild-type mice, these
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mice showed 10-fold higher soluble ICAM-1 (sICAM-1) levels in plasma and elevated circulating neutrophil count. In the models of thioglycollate-induced peritonitis and contact
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hypersensitivity response, the sICAM-1 transgenic mice demonstrated significantly reduced neutrophil infiltration than wild-type controls. In another study, exogenous recombinant sICAM1 reduced leukocyte adhesion to vascular endothelium in ischemia-reperfusion injury in mice
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(Kusterer et al., 1998). Likewise, the intravenous administration of soluble L-selectin has been shown to significantly diminish leukocyte rolling in cremaster muscle postcapillary venules in mice (Ferri et al., 2002). 3.7. Endocan Endocan is a soluble proteoglycan secreted by endothelial cells. The expression of the protein in endothelial cells is regulated by cytokines and pro-inflammatory cytokines TNF- and IL-1 strongly up-regulate endocan mRNA levels (Lassalle et al., 1996). Circulating endocan is found in sera from healthy subjects and is increased in inflammatory conditions. For example, Page 10 of 28
seven-fold increase in circulating endocan levels has been found in patients with a septic shock (Bechard et al., 2000). Endocan binds directly to LFA-1 and inhibits LFA-1/ICAM-1 interaction suggesting that the protein can negatively regulate LFA-1-dependent leukocyte adhesion in vivo (Béchard et al., 2001). Interestingly, lower levels of serum endocan have recently been shown to be associated with a higher incidence of acute lung injury in major trauma patients (Mikkelsen et
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al., 2011). This observation may be explained by endocan-mediated suppression of leukocyte
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recruitment in the lung.
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3.8. Angiostatin
Angiostatin, a proteolytic fragment of plasminogen, contains either the first 3 (K1-3) or
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the first 4 (K1-4) kringle domains of plasminogen. K1-3 and K1-4 interact with leukocyte 1 and
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2 integrins, respectively. Angiostatin thereby inhibits 1 and 2 integrin-mediated adhesion of leukocytes to extracellular matrix proteins and the endothelium as well as their transmigration
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through endothelium in vitro (Chavakis et al., 2005). K1-4 specifically inhibited Mac-1dependent adhesion of neutrophils to immobilized ICAM-1 and inhibited neutrophil recruitment
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in vivo as was observed in the model of thioglycollate-induced acute peritonitis. Angiostatin has been demonstrated to be generated in inflammation both in circulation and tissue (Chavakis et al.,. 2005). Interestingly, the expression of angiostatin forms peaked at the terminal phase of
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wound healing.
3.9. High molecular weight kininogens High molecular weight kininogen (HK) and its cleavage product cleaved HK (HKa) interact with integrin Mac-1 but not LFA-1 and HKa has significantly higher affinity for Mac-1 compared with HK. Cleavage of HK occurs in inflammation and leads to increased plasma HKa levels (Colman et al., 1998). The kininogens have been shown to specifically inhibit Mac-1dependent leukocyte adhesion to fibrinogen and ICAM-1 on endothelial cells in vitro (Chavakis et al., 2001). In a mouse model of thioglycollate-induced peritonitis, intravenous administration Page 11 of 28
of the recombinant domain 5 of HK/HKa which is responsible for the anti-adhesive effect of the proteins decreased neutrophil recruitment by 70% (Chavakis et al., 2001). The extent of the inhibition was comparable to the inhibitory effect observed with an antibody directed to Mac-1. HK deficiency has been reported to be associated with excessive leukocyte emigration in inflammation as was determined by the skin-window technique (Waldmann et al., 1975).
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Because HKa has a higher affinity for Mac-1 than HK and, therefore, has stronger anti-adhesive
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capacity, the elevation of HKa levels in inflammation is likely to increase the anti-adhesive
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properties of the HK/HKa system. 3.10. Syndecan-1 (CD138)
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Syndecan-1 (CD138) is a membrane heparan sulfate proteoglycan which is expressed on endothelial cells, epithelial cells, and leukocytes and up-regulated in inflammation (Elenius et
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al., 1991; Gallo et al., 1996; Wang et al., 2012). Studies on syndecan-1-deficient mice showed
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that the protein negatively regulates neutrophil adhesion to endothelium and inhibits neutrophil influx in inflammatory response. Compared with wild-type mice, syndecan-1-deficient mice
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demonstrated significantly increased neutrophil recruitment in experimental models of colitis, kidney inflammation, and contact allergies (Rops et al., 2007; Kharabi Masouleh et al., 2009; Floer et al., 2010). Syndecan-1-deficient neutrophils displayed increased adhesion to endothelial
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cells in vitro and increased leukocyte adhesion to endothelium in vivo indicating that syndecan-1 interferes with neutrophil-endothelial adhesive interactions (Floer et al., 2010; Götte et al., 2002). The mechanism of the anti-adhesive effect of syndecan-1 is not completely clear. Floer et al. demonstrated an increased interaction of syndecan-1-deficient neutrophils with immobilized ICAM-1 (Floer et al., 2010). In another study, blocking antibodies directed to CD18 were able to reduce increased binding of syndecan-1-deficient neutrophils to ICAM-1 (Kharabi Masouleh et al., 2009). These data suggest that syndecan-1 modulates the direct interaction of ICAM-1 with its integrin counter-receptors.
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3.11. Other anti-adhesive proteins The positive acute phase reactants ceruloplasmin and hemopexin have been reported to suppress neutrophil adhesive interactions in in vitro experiments, but whether these proteins regulate neutrophil recruitment in vivo remains to be proven (Broadley and Hoover, 1989;
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Suzuki et al., 2003). Ceruloplasmin significantly reduced the adhesion of both resting and phorbol myristate acetate (PMA)-activated neutrophils to endothelial cell monolayers (Broadley
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and Hoover, 1989). The inhibitory effect of ceruloplasmin was significant at its physiological
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plasma levels (0.3 mg/ml) and was further increased with the increase of the protein concentration. Hemopexin exerted a strong inhibitory action on Mg2+-dependent adhesion of
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PMA-activated neutrophils to fibrinogen- and serum-coated surfaces suggesting that the protein regulates 2 integrin-dependent cell adhesion (Suzuki et al., 2003). Another positive acute phase
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reactant plasminogen activator inhibitor-1 (PAI-1) has been shown to detach cells from extracellular matrices (Czekay et al., 2003), but whether the protein regulates neutrophil
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adhesion to the endothelium remains to be investigated.
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Interestingly, one established anti-adhesive protein that regulates neutrophil recruitment has been reported to be down-regulated in acute inflammation. Developmental endothelial locus1 (Del-1), a glycoprotein secreted by endothelial cells, associates with endothelial cell surface
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and extracellular matrix but does not circulate in blood (Choi, 2009). Del-1 is a ligand of LFA-1 and antagonizes LFA-1-dependent neutrophil adhesion to the endothelium and neutrophil recruitment in inflammation (Choi et al., 2008). The levels of mRNA encoding Del-1 have been shown to be significantly decreased in LPS-induced lung inflammation, arguing against a proresolving role of the protein in inflammation (Choi et al., 2008). However, Del-1 is not a ubiquitous protein and is expressed by endothelial cells of only a number of tissues, such as lung and gingiva. Therefore, the protein can be considered as a specialized tissue-specific regulator of
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neutrophil adhesion and recruitment which decreased expression in inflammation allows for an efficient inflammatory response in these tissues. 3.12. Proteins with suggested anti-adhesive activity Two positive acute phase reactants, soluble fibrinogen and haptoglobin, could potentially
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act as the anti-adhesive proteins because they are alternative ligands of 2 integrins and,
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therefore, can competitively inhibit 2 integrin-dependent adhesive interactions. Fibrinogen is known to promote leukocyte extravasation and recruitment. First, the protein becomes deposited
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as a provisional matrix in the inflamed regions and serves as a substrate for leukocyte adhesion. Second, besides binding to 2 integrins, fibrinogen has been shown to bind to ICAM-1 and can
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act as a bridging molecule between leukocyte Mac-1 and endothelial ICAM-1 (Languino et al.,
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1993; Duperray et al., 1997). However, theoretically, soluble fibrinogen which is up-regulated up to several-fold in inflammation could compete with both the immobilized and ICAM-1-
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associated fibrinogen and other endothelial 2 integrin counter-receptors for binding with 2 integrins and, thus, inhibit leukocyte-endothelium adhesive interactions. Haptoglobin has been
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shown to bind to integrin Mac-1 on the surface of leukocytes and compete for the binding with other Mac-1 ligands (El Ghmati et al., 1996). Therefore, haptoglobin can probably act as a competitive inhibitor of neutrophil adhesion by interfering with the interaction of Mac-1 with its
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endothelial counter-receptors.
4. Concluding remarks and summary Neutrophil adhesion to the endothelium represents an important checkpoint in the cell
recruitment into inflamed tissues and is tightly controlled. At the onset of the inflammatory response, up-regulated expression of cell adhesion molecules which mediate neutrophilendothelial interactions enables efficient neutrophil extravasation and migration into the inflamed tissues. However, inflammation also triggers up-regulation of proteins which interfere
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with neutrophil adhesion to the endothelium thereby preventing further neutrophil recruitment. The non-redundant role of the anti-adhesive proteins in dampening inflammation has been demonstrated in experiments with knockout animals which exhibited increased magnitude and duration of acute inflammatory response. Therefore, the up-regulation of the anti-adhesive proteins in inflammation can represent a pro-resolving mechanism that actively prevents
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neutrophil recruitment in resolution of inflammation.
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In resolving acute inflammation, tissue neutrophil accumulation is rapid and can peak at
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as early as several hours after triggering the inflammatory response followed by a gradual decrease of the cell number in the inflamed tissue. This suggests that the pro-resolving
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mechanisms which prevent and reverse the tissue neutrophil accumulation are induced early in the inflammatory response. It is noteworthy that some of the anti-adhesive proteins, such as
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PTX3 and CRP, can be strongly up-regulated within hours in response to an inflammatory event suggesting that the proteins not only contribute to but may initiate the resolution. Another point
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that should be emphasized is that many of the anti-adhesive proteins are positive acute phase reactants which are released into the circulation in response to unspecific inflammatory stimuli.
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Therefore, in contrast to pro-resolving lipid mediators which are produced locally, the upregulation of the anti-adhesive proteins in inflammation may represent a systemic anti-
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inflammatory response.
In summary, inflammation triggers up-regulation of proteins which can interfere with
neutrophil-endothelial adhesive interaction and, therefore, act as a barrier in neutrophil extravasation and migration into the inflamed tissue. The up-regulation of such anti-adhesive proteins in inflammation can represent a mechanism for preventing the entry of neutrophils into sites of resolving inflammation. This potential mechanism of the resolution of inflammation is likely to act additively and in concert with other ones to restore tissue neutrophil homeostasis in resolving inflammation.
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Acknowledgements This work was supported by the Russian Foundation for Basic Research. References
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Figure legends Fig. 1. The mechanisms that resolve neutrophil-mediated inflammation. A. Restoration of tissue neutrophil homeostasis in resolving inflammation. Neutrophils are rapidly recruited into sites of infection or injury by chemokines produced by the inflamed tissue (1). In contrast, the
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resolution of inflammation requires restoration of neutrophil homeostasis in the inflamed tissue that is achieved by several mechanisms, such as phagocytosis of apoptotic neutrophils by
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macrophages (2), neutrophil emigration from the inflamed area (3), normalization of chemokine
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gradients in the inflamed area (4), and generation of pro-resolving lipids which suppress further neutrophil influx (5). B. Inflammation-triggered up-regulation of anti-adhesive proteins as a pro-
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resolving mechanism. Inflammation rapidly enhances surface expression of endothelial cell adhesion molecules which mediate neutrophil extravasation and recruitment into inflamed
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tissues. In addition, inflammation up-regulates vascular levels of anti-adhesive proteins that
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prevent further neutrophil infiltration by blocking the cell egress from the circulation. Table 1. Anti-adhesive proteins which are up-regulated in inflammation and disrupt
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neutrophil adhesion to the endothelium.
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Figure
A
The non-inflamed state
The onset of inflammation
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Figure 1
The resolution of inflammation
Blood flow
...
1
Chemokines
The non-inflamed state
The onset of inflammation
Postcapillary venule Rolling
Blood flow
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an
Inflamed tissue
Arrest
...
2
Efferocytosis
The resolution of inflammation – cell adhesion molecules – anti-adhesive proteins
Diapedesis
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Neutrophil
* **
Pro-resolving lipids
Non-inflamed tissue
4
Vessel lumen
Migration into inflamed tissue
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Endothelium
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B
3
5
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Neutrophil
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Postcapillary venule
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Table
Table 1
Levels in inflammati on
Effect of the protein knockout
Effect of the protein Mechanism of the antioverexpression / i.v. adhesive effect administration
References
Pentraxin 3 (PTX3)
Increased neutrophil recruitment
Reduced neutrophil recruitment
19-22
C-reactive protein (CRP)
?
Reduced neutrophil recruitment
1-Acid glycoprotein (AGP)
?
Reduced neutrophil recruitment
Galectin-1
Increased neutrophil recruitment
Reduced neutrophil recruitment
Annexin 1
Increased neutrophil recruitment
sICAM-1
–
sL-selectin
Endocan
us
cr
Competitive inhibition of P-selectin-dependent rolling
23-27
Competitive inhibition of sLex- dependent rolling (?); NO-dependent inhibition of rolling and adhesion
28-31
Inhibition of neutrophil activation (?)
32-36
Reduced neutrophil recruitment
?
37-44
Reduced neutrophil recruitment
Competitive inhibition of Mac-1- and LFA-1dependent adhesion
45-48
–
Reduced leukocyte rolling
Competitive inhibition of L-selectin-dependent rolling
45,46,49
?
?
Competitive inhibition of LFA-1-dependent adhesion
50-53
pt
ed
M
an
Down-regulation of Lselectin surface expression
ce
Ac
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Antiadhesive protein
Angiostatin
?
Reduced neutrophil recruitment
Competitive inhibition of Mac-1-dependent adhesion
54
High molecular weight kininogens
(HK) (HKa)
Increased neutrophil recruitment
Reduced neutrophil recruitment
Competitive inhibition of Mac-1-dependent adhesion
55-57
Syndecan-1 (CD138)
Increased neutrophil recruitment
?
?
58-64
Page 28 of 28
S0171-2985(13)00041-7 http://dx.doi.org/doi:10.1016/j.imbio.2013.03.001 IMBIO 51010
To appear in: Received date: Revised date: Accepted date:
7-11-2012 2-3-2013 2-3-2013
Please cite this article as: Pliyev, B.K., Anti-adhesive proteins and resolution of neutrophil-mediated inflammation, Immunobiology (2013), http://dx.doi.org/10.1016/j.imbio.2013.03.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
*Manuscript
Anti-adhesive proteins and resolution of neutrophil-mediated inflammation Boris K. Pliyev1,* 1
, Institute of Immunology, Kashirskoye Shosse 24-2, Moscow 115478, Russia,
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*, corresponding author:
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Boris K. Pliyev, PhD
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Institute of Immunology Kashirskoye Shosse 24-2
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Moscow 115478, Russia
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Tel.: 7-499-617-7649
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Fax: 7-499-617-1027
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E-mail: [email protected]
Page 1 of 28
Abstract The onset of inflammatory response is associated with neutrophil recruitment into infected or injured tissues, whereas the resolution of inflammation, on the contrary, requires blockade of further recruitment and clearance of the recruited cells. Adhesion of circulating
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neutrophils to the endothelium represents a crucial step in their recruitment into the inflamed tissues. Previous studies have identified a number of proteins which can interfere with
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neutrophil-endothelial adhesive interactions and act as natural inhibitors of the leukocyte egress
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from the circulation. Essentially, these proteins are up-regulated in inflammation and, therefore, have potential pro-resolving activity. Knockout animals deficient in the anti-adhesive proteins
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demonstrated increased magnitude and duration of acute inflammation indicating that the proteins play a non-redundant role in dampening the inflammatory response. This paper is a
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review of the experimental data supporting the hypothesis that the up-regulation of the anti-
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resolution of inflammation.
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adhesive proteins may represent an anti-inflammatory mechanism that contributes to the
Key words: inflammation, resolution, neutrophils, anti-adhesive proteins
Page 2 of 28
1. Introduction A hallmark of inflammation is the recruitment of leukocytes to infected or injured tissues. Neutrophils are the first cells that arrive at sites of infection or injury and play a key role in the inflammatory response (Mantovani et al., 2011). Acute inflammatory response is a finite self-
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resolving process and is accompanied by a transient neutrophil recruitment, whereas in nonresolving chronic inflammation, the recruitment may continue over months or years. Restoration
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of tissue neutrophil homeostasis is considered to be a critical event in the resolution of
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inflammation (Bratton and Henson, 2011). Consequently, the resolution phase is defined as the interval from maximal neutrophilic infiltration to the point when they are lost from the tissue
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(Serhan et al., 2007). It is now accepted that the resolution process is active, rather than passive, and is controlled by a number of mechanisms which are switched on in the course of resolving
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inflammation. The established pro-resolving mechanisms include tissue neutrophil apoptosis followed by phagocytosis of the apoptotic cells by macrophages, retrograde neutrophil migration
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from the inflamed area and generation of lipid mediators which block the ongoing neutrophil recruitment. Results from previous studies raise the hypothesis that the pro-resolving
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mechanisms may also involve inflammation-triggered up-regulation of proteins that block and/or disrupt neutrophil-endothelial cell interactions and thereby prevent neutrophil recruitment. In the following sections, I will briefly overview the established mechanisms which restore tissue
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neutrophil homeostasis in resolving inflammation and will consider the experimental data supporting the hypothesis that the up-regulation of the anti-adhesive proteins may represent an essential pro-resolving mechanism. 2. Restoration of tissue neutrophil homeostasis in resolving inflammation Regulated apoptosis of neutrophils in an inflamed tissue followed by their phagocytosis (efferocytosis) by recruited monocyte-derived macrophages is considered to be one of the major mechanisms which are responsible for tissue neutrophil clearance in resolving inflammation
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(Bratton and Henson, 2011). In addition, neutrophils have been shown to traffic bidirectionally between sites of inflammation and the vasculature and the retrograde neutrophil migration to the vasculature has been suggested to be an alternative mechanism by which inflammation is resolved (Hughes et al., 1997; Mathias et al., 2006). Moreover, neutrophil migration across the epithelium into luminal spaces may also contribute to the cell clearance from the tissue. For
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example, neutrophil egress into airspaces is considered as a possible mechanism that resolves
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airway inflammation (Uller et al., 2006). Interestingly, neutrophil emigration from the inflamed tissue can exceed neutrophil clearance by apoptosis (Hughes et al., 1997). Thus, neutrophil
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egress from the inflamed tissue can complement regulated neutrophil apoptosis to restore tissue
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neutrophil homeostasis and to resolve inflammation (Fig. 1A).
To quench tissue neutrophilia in the inflamed area, the elimination/efflux of the recruited
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neutrophils is not enough. The ongoing neutrophil infiltration into the tissue must also be halted. The mechanisms that negatively regulate neutrophil recruitment in resolving inflammation are
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not completely understood. The cessation of neutrophil influx can be achieved by mechanisms that normalize chemokine gradients which cause neutrophil recruitment and/or mechanisms that
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actively prevent neutrophil migration into inflamed tissues. The former depend on reversion of chemoattractant-producing parenchymal/stromal cells that hosted the inflammatory event back to a non-inflammatory phenotype (Filer et al., 2006). For example, macrophages ingesting
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apoptotic neutrophils produce anti-inflammatory mediators, such as IL-10 and TGF-, which can restore non-inflammatory stromal microenvironment (Fox et al., 2010). However, the mechanisms exist that actively counteract neutrophil recruitment in resolving inflammation. An established mechanism that actively suppresses neutrophil recruitment in the course of the inflammatory response is generation of specialized anti-inflammatory lipid mediators which represent local stop signals preventing further or excessive neutrophil entry into tissue (Fig.1A). Endogenous lipid mediators with anti-inflammatory and pro-resolving activity include
Page 4 of 28
lipoxins, which are biosynthesized from arachidonic acid, and omega-3 polyunsaturated fatty acid-derived resolvins, protectins and maresins (Norling and Serhan, 2010). The antiinflammatory lipid mediators have been shown to inhibit neutrophil transendothelial migration in vitro and reduce neutrophil infiltration into inflamed tissues in models of acute inflammation in vivo, thereby dampening the inflammatory response (Serhan et al., 2006; Serhan, 2007; Sun et
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al., 2007; Serhan et al., 2012). Besides the generation of the anti-inflammatory lipids, other
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mechanisms may suppress neutrophil recruitment in resolving inflammation. One of such mechanisms can be up-regulation of anti-adhesive proteins which disrupt neutrophil-endothelial
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adhesive interactions and thus prevent neutrophil egress from the circulation (Fig. 1B).
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3. Anti-adhesive proteins as negative regulators of neutrophil recruitment in resolving inflammation
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Early in the inflammatory response, cytokines and chemoattractants produced in an
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inflamed tissue activate the microvascular endothelium resulting in induction of cell adhesion molecules within the local microcirculation. The up-regulated cell adhesion molecules mediate
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chemoattractant-induced neutrophil adhesion to the inflamed endothelium and subsequent transendothelial migration. The molecular mechanisms involved in neutrophil-endothelial cell adhesive interactions have been extensively reviewed elsewhere (Ley et al., 2007). Briefly,
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sequential initial steps of neutrophil-endothelial interactions are tethering, rolling, activation and firm adhesion (arrest). Neutrophil tethering and rolling are mediated by selectins; L-selectin is expressed constitutively on leukocytes, whereas activated endothelial cells express E- and Pselectins. The selectins interact with their counter-receptors on leukocytes and endothelial cells (Rosen, 2004; Zarbock et al., 2011). Subsequent firm adhesion of neutrophils to the endothelium is predominantly mediated by β2 integrins LFA-1 (L2) and Mac-1 (M2) (Smith et al., 1989; Ley et al., 2007). Neutrophil activation by chemoattractants and cytokines produced by the inflamed tissue induces conformational changes in β2 integrins necessary for enhanced ligand
Page 5 of 28
recognition. The activated LFA-1 and Mac-1 firmly bind to their major counter-receptor intercellular cell adhesion molecule-1 (ICAM-1) on endothelial cells. Results of numerous studies indicate that, besides the up-regulation of the cell adhesion molecules which mediate neutrophil extravasation, inflammation also triggers up-regulation of
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proteins which can inhibit neutrophil-endothelial adhesive interactions and, thus, act as negative regulators of the leukocyte egress from the circulation (Table 1). Knockout mice deficient in the
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anti-adhesive proteins demonstrated increased magnitude and duration of acute inflammation,
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whereas overexpression or intravenous injection of the proteins significantly attenuated neutrophil recruitment and quenched the inflammatory response in experimental models of
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inflammation. These data indicate that the anti-adhesive proteins play an important role in dampening the inflammatory response in vivo. Therefore, the up-regulation of the anti-adhesive
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proteins in inflammation can potentially be considered as a mechanism that complements the induction of pro-resolving lipids to prevent neutrophil recruitment in resolving inflammation
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(Fig. 1B). Of note, many of the proteins listed in Table 1 belong to classical positive acute phase reactants which expression and release into the circulation are up-regulated in response to
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bacterial infections, wounding and other unspecific inflammatory stimuli (Gabay and Kushner, 1999). Below, I will review the anti-adhesive proteins and the experimental data that demonstrate their essential role in negative regulation of neutrophil recruitment in resolving
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inflammation.
3.1. Pentraxin 3 (PTX3) Pentraxin 3 (PTX3) is an acute phase protein secreted by various cells including leukocytes and endothelial cells. Its plasma levels in humans are very low in normal conditions (2 ng/ml) but increase rapidly (peak at 6-8 hours) and dramatically (up to 200-800 ng/ml) during sepsis, endotoxic shock and other inflammatory and infectious conditions, correlating with the severity of the disease (Mantovani et al., 2008). PTX3 has been shown to bind to P-
Page 6 of 28
selectin and inhibits P-selectin-dependent neutrophil rolling (Deban et al., 2010). Consistent with its anti-adhesive property, the protein exerted anti-inflammatory effects in various experimental models of acute inflammation. For example, administration of exogenous recombinant PTX3 to mice inhibited acid-induced recruitment of neutrophils to the lungs and chemokine-induced entry of neutrophils into the pleural cavity to the same extent as antibody blockade or genetic
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deficiency in P-selectin (Deban et al., 2010). Moreover, PTX3-deficient mice have been shown
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to be more susceptible to ischemia-reperfusion injury and LPS-induced acute lung injury, and the increased inflammation-induced tissue injury in PTX3-deficient mice was associated with the
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increased neutrophil recruitment in the inflamed tissues (Salio et al., 2008; Han et al., 2011).
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3.2. C-reactive protein (CRP)
The pentraxin C-reactive protein (CRP) is the most characteristic acute phase protein in
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humans. In healthy individuals, plasma concentration of CRP is less than 1 µg/ml, but it can
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rapidly (within hours) increase up to 1,000-fold in response to an inflammatory event peaking at 24 - 48 hours after the induction of inflammation (Marnell et al., 2005). The magnitude of the
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CRP response in humans is related to the severity of inflammation or the extent of tissue injury. CRP has been shown to inhibit neutrophil recruitment in inflammation. For example, in experimental models of alveolitis, transgenic mice with high plasma levels of CRP exhibited
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diminished neutrophil infiltration compared with normal mice (Heuertz et al., 1993). In the same model of inflammation, intravenous administration of recombinant CRP significantly reduced neutrophil recruitment in rabbits (Heuertz et al., 1994). In in vitro experiments, CRP markedly attenuated neutrophil adhesion to endothelial cells and induced shedding of L-selectin from neutrophil plasma membrane without inducing generalized neutrophil activation (Zouki et al., 1997; El Kebir et al., 2011). The anti-adhesive effect of CRP was prevented by inhibition of Lselectin shedding indicating that CRP inhibits neutrophil-endothelial interaction by decreasing the surface expression of L-selectin (Zouki et al., 1997).
Page 7 of 28
3.3. 1-Acid glycoprotein (AGP) 1-Acid glycoprotein (AGP) is one of the major positive acute phase reactants. In humans, the normal average plasma levels of AGP are 0.5-1 mg/ml, whereas in disease it can reach 3 mg/ml (Ceciliani and Pocacqua, 2007). The protein is not only up-regulated during
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inflammation, but also undergoes structural modifications of its oligosaccharide moiety. Strikingly, acute inflammation induces a strong increase in AGP molecules bearing sialyl Lewisx
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(sLex), the minimal carbohydrate epitope recognized by all three selectins. The sLex-bearing
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AGP glycoforms persist at a high level throughout the inflammatory period suggesting that they may competitively interfere with leukocyte rolling in inflammation (De Graaf et al., 1993).
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Indeed, these AGP glycoforms have been shown to inhibit the adhesion of sLex-expressing cells to immobilized E-selectin (Jørgensen et al., 1998). AGP, when administered intravenously,
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inhibited carrageenan-induced neutrophil recruitment into the rat peritoneal cavity (Mestriner et al., 2007). Intravital microscopy demonstrated that AGP inhibited rolling and adhesion of
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leukocytes in the mesenteric microcirculation. The inhibitory effect of AGP was blocked by aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS), and was not observed in
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iNOS-deficient mice suggesting that AGP affects leukocyte recruitment via NO-dependent mechanism (Mestriner et al., 2007).
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3.4. Galectin-1
Galectin-1 is a mammalian lectin expressed by a variety of cell types and is up-regulated
in inflammatory conditions (Baum et al., 1995; Iqbal et al., 2011; Stancic et al., 2011). The protein inhibits neutrophil-endothelial adhesive interactions and acts as an endogenous regulator of neutrophil trafficking in inflammatory response. For example, in a model of IL-1-induced peritonitis in mice, exogenous galectin-1 reduced leukocyte adhesion and emigration in the mesenteric microcirculation (La et al., 2003). In another study, IL-1-induced neutrophil adhesion and emigration were increased in the cremasteric circulation of galectin-1-deficient
Page 8 of 28
mice compared with wild-type animals (Cooper et al., 2008). Galectin-1 has been shown to inhibit chemoattractant-induced neutrophil activation suggesting that this may represent a mechanism of the anti-adhesive effect of the protein (Cooper et al., 2008). Human neutrophils express little if any detectable galectin-1, but bind the exogenous protein. Preincubation of neutrophils with recombinant galectin-1 significantly decreased the extent of rolling and
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adhesion of the cells on activated endothelium (Cooper et al., 2008). Endothelial cells, in
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contrast to neutrophils, express high amounts of galectin-1 and its expression is up-regulated by proinflammatory cytokines (Baum et al., 1995; La et al., 2003). Small interfering RNA-mediated
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knockdown of galectin-1 in endothelial cells resulted in an increase in neutrophil rolling and adhesion on activated endothelium, suggesting that endogenous galectin-1 presented by the
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endothelium acts as negative regulator of neutrophil adhesion (Cooper et al., 2008).
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3.5. Annexin 1
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Annexin 1 is constitutively expressed by many cell types and is up-regulated in response to inflammatory stimuli (Solito et al., 1998; Yang et al., 1999; Särndahl et al., 2010). The effects
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of annexin 1 on neutrophil trafficking were tested in a variety of experimental animal models of inflammation: the administration of the recombinant protein exerted an anti-inflammatory effect and dampened neutrophil recruitment, whereas annexin 1-deficient mice displayed a higher
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degree of neutrophil infiltration compared with wild-type mice (Lim et al., 1998; La et al., 2001; Chatterjee et al., 2005). Exogenous annexin 1 has been shown to inhibit neutrophil firm adhesion to the endothelium both in vitro and in vivo (Lim et al., 1998; Hayhoe et al., 2006). Neutrophils contain extensive intracellular pool of annexin 1 which is localized predominantly in gelatinase granules and is mobilized onto the cell surface when neutrophils adhere to the endothelium (Perretti and Flower; 2004). The mobilized protein exerts the anti-adhesive effect in an autocrine/paracrine fashion via formyl-peptide receptor-like 1 (FPRL1), a leukocyte receptor for annexin 1 (Hayhoe et al., 2006). The protein expression in circulating neutrophils has been reported to be significantly increased in inflammation, suggesting that, in resolving Page 9 of 28
inflammation, neutrophils can negatively regulate their own recruitment by producing larger amounts of annexin 1 upon interaction with the endothelium (Särndahl et al., 2010). 3.6. Soluble adhesion molecules (soluble selectins and ICAM-1) The cell adhesion molecules involved in neutrophil-endothelial interactions, such as
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selectins and ICAM-1, can be shed from the cell surface and the shedding is increased in various inflammatory conditions elevating the plasma levels of the soluble forms (Giddings; 2005). The
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soluble adhesion molecules can competitively inhibit the adhesive interactions of their
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membrane counterparts, thus interfering with neutrophil-endothelial adhesive interactions. Indeed, soluble selectins and ICAM-1 have been identified as major factors responsible for the
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inhibitory effect of normal plasma on neutrophil adhesion to the endothelium in vitro (Ohno et al., 1997). Wang et al. generated a transgenic mouse model overexpressing the extracellular
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domain of mouse ICAM-1 in the liver (Wang et al., 2005). Compared with wild-type mice, these
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mice showed 10-fold higher soluble ICAM-1 (sICAM-1) levels in plasma and elevated circulating neutrophil count. In the models of thioglycollate-induced peritonitis and contact
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hypersensitivity response, the sICAM-1 transgenic mice demonstrated significantly reduced neutrophil infiltration than wild-type controls. In another study, exogenous recombinant sICAM1 reduced leukocyte adhesion to vascular endothelium in ischemia-reperfusion injury in mice
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(Kusterer et al., 1998). Likewise, the intravenous administration of soluble L-selectin has been shown to significantly diminish leukocyte rolling in cremaster muscle postcapillary venules in mice (Ferri et al., 2002). 3.7. Endocan Endocan is a soluble proteoglycan secreted by endothelial cells. The expression of the protein in endothelial cells is regulated by cytokines and pro-inflammatory cytokines TNF- and IL-1 strongly up-regulate endocan mRNA levels (Lassalle et al., 1996). Circulating endocan is found in sera from healthy subjects and is increased in inflammatory conditions. For example, Page 10 of 28
seven-fold increase in circulating endocan levels has been found in patients with a septic shock (Bechard et al., 2000). Endocan binds directly to LFA-1 and inhibits LFA-1/ICAM-1 interaction suggesting that the protein can negatively regulate LFA-1-dependent leukocyte adhesion in vivo (Béchard et al., 2001). Interestingly, lower levels of serum endocan have recently been shown to be associated with a higher incidence of acute lung injury in major trauma patients (Mikkelsen et
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al., 2011). This observation may be explained by endocan-mediated suppression of leukocyte
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recruitment in the lung.
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3.8. Angiostatin
Angiostatin, a proteolytic fragment of plasminogen, contains either the first 3 (K1-3) or
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the first 4 (K1-4) kringle domains of plasminogen. K1-3 and K1-4 interact with leukocyte 1 and
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2 integrins, respectively. Angiostatin thereby inhibits 1 and 2 integrin-mediated adhesion of leukocytes to extracellular matrix proteins and the endothelium as well as their transmigration
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through endothelium in vitro (Chavakis et al., 2005). K1-4 specifically inhibited Mac-1dependent adhesion of neutrophils to immobilized ICAM-1 and inhibited neutrophil recruitment
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in vivo as was observed in the model of thioglycollate-induced acute peritonitis. Angiostatin has been demonstrated to be generated in inflammation both in circulation and tissue (Chavakis et al.,. 2005). Interestingly, the expression of angiostatin forms peaked at the terminal phase of
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wound healing.
3.9. High molecular weight kininogens High molecular weight kininogen (HK) and its cleavage product cleaved HK (HKa) interact with integrin Mac-1 but not LFA-1 and HKa has significantly higher affinity for Mac-1 compared with HK. Cleavage of HK occurs in inflammation and leads to increased plasma HKa levels (Colman et al., 1998). The kininogens have been shown to specifically inhibit Mac-1dependent leukocyte adhesion to fibrinogen and ICAM-1 on endothelial cells in vitro (Chavakis et al., 2001). In a mouse model of thioglycollate-induced peritonitis, intravenous administration Page 11 of 28
of the recombinant domain 5 of HK/HKa which is responsible for the anti-adhesive effect of the proteins decreased neutrophil recruitment by 70% (Chavakis et al., 2001). The extent of the inhibition was comparable to the inhibitory effect observed with an antibody directed to Mac-1. HK deficiency has been reported to be associated with excessive leukocyte emigration in inflammation as was determined by the skin-window technique (Waldmann et al., 1975).
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Because HKa has a higher affinity for Mac-1 than HK and, therefore, has stronger anti-adhesive
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capacity, the elevation of HKa levels in inflammation is likely to increase the anti-adhesive
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properties of the HK/HKa system. 3.10. Syndecan-1 (CD138)
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Syndecan-1 (CD138) is a membrane heparan sulfate proteoglycan which is expressed on endothelial cells, epithelial cells, and leukocytes and up-regulated in inflammation (Elenius et
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al., 1991; Gallo et al., 1996; Wang et al., 2012). Studies on syndecan-1-deficient mice showed
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that the protein negatively regulates neutrophil adhesion to endothelium and inhibits neutrophil influx in inflammatory response. Compared with wild-type mice, syndecan-1-deficient mice
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demonstrated significantly increased neutrophil recruitment in experimental models of colitis, kidney inflammation, and contact allergies (Rops et al., 2007; Kharabi Masouleh et al., 2009; Floer et al., 2010). Syndecan-1-deficient neutrophils displayed increased adhesion to endothelial
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cells in vitro and increased leukocyte adhesion to endothelium in vivo indicating that syndecan-1 interferes with neutrophil-endothelial adhesive interactions (Floer et al., 2010; Götte et al., 2002). The mechanism of the anti-adhesive effect of syndecan-1 is not completely clear. Floer et al. demonstrated an increased interaction of syndecan-1-deficient neutrophils with immobilized ICAM-1 (Floer et al., 2010). In another study, blocking antibodies directed to CD18 were able to reduce increased binding of syndecan-1-deficient neutrophils to ICAM-1 (Kharabi Masouleh et al., 2009). These data suggest that syndecan-1 modulates the direct interaction of ICAM-1 with its integrin counter-receptors.
Page 12 of 28
3.11. Other anti-adhesive proteins The positive acute phase reactants ceruloplasmin and hemopexin have been reported to suppress neutrophil adhesive interactions in in vitro experiments, but whether these proteins regulate neutrophil recruitment in vivo remains to be proven (Broadley and Hoover, 1989;
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Suzuki et al., 2003). Ceruloplasmin significantly reduced the adhesion of both resting and phorbol myristate acetate (PMA)-activated neutrophils to endothelial cell monolayers (Broadley
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and Hoover, 1989). The inhibitory effect of ceruloplasmin was significant at its physiological
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plasma levels (0.3 mg/ml) and was further increased with the increase of the protein concentration. Hemopexin exerted a strong inhibitory action on Mg2+-dependent adhesion of
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PMA-activated neutrophils to fibrinogen- and serum-coated surfaces suggesting that the protein regulates 2 integrin-dependent cell adhesion (Suzuki et al., 2003). Another positive acute phase
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reactant plasminogen activator inhibitor-1 (PAI-1) has been shown to detach cells from extracellular matrices (Czekay et al., 2003), but whether the protein regulates neutrophil
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adhesion to the endothelium remains to be investigated.
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Interestingly, one established anti-adhesive protein that regulates neutrophil recruitment has been reported to be down-regulated in acute inflammation. Developmental endothelial locus1 (Del-1), a glycoprotein secreted by endothelial cells, associates with endothelial cell surface
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and extracellular matrix but does not circulate in blood (Choi, 2009). Del-1 is a ligand of LFA-1 and antagonizes LFA-1-dependent neutrophil adhesion to the endothelium and neutrophil recruitment in inflammation (Choi et al., 2008). The levels of mRNA encoding Del-1 have been shown to be significantly decreased in LPS-induced lung inflammation, arguing against a proresolving role of the protein in inflammation (Choi et al., 2008). However, Del-1 is not a ubiquitous protein and is expressed by endothelial cells of only a number of tissues, such as lung and gingiva. Therefore, the protein can be considered as a specialized tissue-specific regulator of
Page 13 of 28
neutrophil adhesion and recruitment which decreased expression in inflammation allows for an efficient inflammatory response in these tissues. 3.12. Proteins with suggested anti-adhesive activity Two positive acute phase reactants, soluble fibrinogen and haptoglobin, could potentially
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act as the anti-adhesive proteins because they are alternative ligands of 2 integrins and,
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therefore, can competitively inhibit 2 integrin-dependent adhesive interactions. Fibrinogen is known to promote leukocyte extravasation and recruitment. First, the protein becomes deposited
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as a provisional matrix in the inflamed regions and serves as a substrate for leukocyte adhesion. Second, besides binding to 2 integrins, fibrinogen has been shown to bind to ICAM-1 and can
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act as a bridging molecule between leukocyte Mac-1 and endothelial ICAM-1 (Languino et al.,
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1993; Duperray et al., 1997). However, theoretically, soluble fibrinogen which is up-regulated up to several-fold in inflammation could compete with both the immobilized and ICAM-1-
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associated fibrinogen and other endothelial 2 integrin counter-receptors for binding with 2 integrins and, thus, inhibit leukocyte-endothelium adhesive interactions. Haptoglobin has been
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shown to bind to integrin Mac-1 on the surface of leukocytes and compete for the binding with other Mac-1 ligands (El Ghmati et al., 1996). Therefore, haptoglobin can probably act as a competitive inhibitor of neutrophil adhesion by interfering with the interaction of Mac-1 with its
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endothelial counter-receptors.
4. Concluding remarks and summary Neutrophil adhesion to the endothelium represents an important checkpoint in the cell
recruitment into inflamed tissues and is tightly controlled. At the onset of the inflammatory response, up-regulated expression of cell adhesion molecules which mediate neutrophilendothelial interactions enables efficient neutrophil extravasation and migration into the inflamed tissues. However, inflammation also triggers up-regulation of proteins which interfere
Page 14 of 28
with neutrophil adhesion to the endothelium thereby preventing further neutrophil recruitment. The non-redundant role of the anti-adhesive proteins in dampening inflammation has been demonstrated in experiments with knockout animals which exhibited increased magnitude and duration of acute inflammatory response. Therefore, the up-regulation of the anti-adhesive proteins in inflammation can represent a pro-resolving mechanism that actively prevents
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neutrophil recruitment in resolution of inflammation.
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In resolving acute inflammation, tissue neutrophil accumulation is rapid and can peak at
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as early as several hours after triggering the inflammatory response followed by a gradual decrease of the cell number in the inflamed tissue. This suggests that the pro-resolving
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mechanisms which prevent and reverse the tissue neutrophil accumulation are induced early in the inflammatory response. It is noteworthy that some of the anti-adhesive proteins, such as
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PTX3 and CRP, can be strongly up-regulated within hours in response to an inflammatory event suggesting that the proteins not only contribute to but may initiate the resolution. Another point
ed
that should be emphasized is that many of the anti-adhesive proteins are positive acute phase reactants which are released into the circulation in response to unspecific inflammatory stimuli.
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Therefore, in contrast to pro-resolving lipid mediators which are produced locally, the upregulation of the anti-adhesive proteins in inflammation may represent a systemic anti-
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inflammatory response.
In summary, inflammation triggers up-regulation of proteins which can interfere with
neutrophil-endothelial adhesive interaction and, therefore, act as a barrier in neutrophil extravasation and migration into the inflamed tissue. The up-regulation of such anti-adhesive proteins in inflammation can represent a mechanism for preventing the entry of neutrophils into sites of resolving inflammation. This potential mechanism of the resolution of inflammation is likely to act additively and in concert with other ones to restore tissue neutrophil homeostasis in resolving inflammation.
Page 15 of 28
Acknowledgements This work was supported by the Russian Foundation for Basic Research. References
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Figure legends Fig. 1. The mechanisms that resolve neutrophil-mediated inflammation. A. Restoration of tissue neutrophil homeostasis in resolving inflammation. Neutrophils are rapidly recruited into sites of infection or injury by chemokines produced by the inflamed tissue (1). In contrast, the
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resolution of inflammation requires restoration of neutrophil homeostasis in the inflamed tissue that is achieved by several mechanisms, such as phagocytosis of apoptotic neutrophils by
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macrophages (2), neutrophil emigration from the inflamed area (3), normalization of chemokine
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gradients in the inflamed area (4), and generation of pro-resolving lipids which suppress further neutrophil influx (5). B. Inflammation-triggered up-regulation of anti-adhesive proteins as a pro-
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resolving mechanism. Inflammation rapidly enhances surface expression of endothelial cell adhesion molecules which mediate neutrophil extravasation and recruitment into inflamed
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tissues. In addition, inflammation up-regulates vascular levels of anti-adhesive proteins that
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prevent further neutrophil infiltration by blocking the cell egress from the circulation. Table 1. Anti-adhesive proteins which are up-regulated in inflammation and disrupt
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neutrophil adhesion to the endothelium.
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Figure
A
The non-inflamed state
The onset of inflammation
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Figure 1
The resolution of inflammation
Blood flow
...
1
Chemokines
The non-inflamed state
The onset of inflammation
Postcapillary venule Rolling
Blood flow
M
an
Inflamed tissue
Arrest
...
2
Efferocytosis
The resolution of inflammation – cell adhesion molecules – anti-adhesive proteins
Diapedesis
ed
Neutrophil
* **
Pro-resolving lipids
Non-inflamed tissue
4
Vessel lumen
Migration into inflamed tissue
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Endothelium
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B
3
5
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Neutrophil
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Postcapillary venule
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Table
Table 1
Levels in inflammati on
Effect of the protein knockout
Effect of the protein Mechanism of the antioverexpression / i.v. adhesive effect administration
References
Pentraxin 3 (PTX3)
Increased neutrophil recruitment
Reduced neutrophil recruitment
19-22
C-reactive protein (CRP)
?
Reduced neutrophil recruitment
1-Acid glycoprotein (AGP)
?
Reduced neutrophil recruitment
Galectin-1
Increased neutrophil recruitment
Reduced neutrophil recruitment
Annexin 1
Increased neutrophil recruitment
sICAM-1
–
sL-selectin
Endocan
us
cr
Competitive inhibition of P-selectin-dependent rolling
23-27
Competitive inhibition of sLex- dependent rolling (?); NO-dependent inhibition of rolling and adhesion
28-31
Inhibition of neutrophil activation (?)
32-36
Reduced neutrophil recruitment
?
37-44
Reduced neutrophil recruitment
Competitive inhibition of Mac-1- and LFA-1dependent adhesion
45-48
–
Reduced leukocyte rolling
Competitive inhibition of L-selectin-dependent rolling
45,46,49
?
?
Competitive inhibition of LFA-1-dependent adhesion
50-53
pt
ed
M
an
Down-regulation of Lselectin surface expression
ce
Ac
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Antiadhesive protein
Angiostatin
?
Reduced neutrophil recruitment
Competitive inhibition of Mac-1-dependent adhesion
54
High molecular weight kininogens
(HK) (HKa)
Increased neutrophil recruitment
Reduced neutrophil recruitment
Competitive inhibition of Mac-1-dependent adhesion
55-57
Syndecan-1 (CD138)
Increased neutrophil recruitment
?
?
58-64
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