Evasins: Tick Salivary Proteins that Inhibit Mammalian Chemokines
2019; Elsevier BV; Volume: 45; Issue: 2 Linguagem: Inglês
10.1016/j.tibs.2019.10.003
ISSN1362-4326
AutoresRam Prasad Bhusal, James R. O. Eaton, Sayeeda Tasneem Chowdhury, Christopher Power, Amanda E. I. Proudfoot, Martin J. Stone, Shoumo Bhattacharya,
Tópico(s)Immunotherapy and Immune Responses
ResumoChemokines are mammalian proteins that are secreted at the sites of tissue insult and stimulate trafficking of leukocytes to the affected tissues, a key component of the inflammatory response.Evasins are tick salivary glycoproteins that bind to chemokines, thereby suppressing the host inflammatory response, an apparent mechanism to prolong the residence times of ticks on their hosts.Bioinformatics searches of salivary transcriptomic and genomic sequence databases and yeast surface display screening methods have enabled discovery of Evasins produced by numerous tick species spread across at least three genera.Two families of Evasins (Classes A and B) have been identified. Evasins from the two families have different 3D structures, different conserved sequence features (including patterns of disulfide bonds), and selectivity for different families of chemokines (CC and CXC, respectively).Evasins each bind to several (or many) chemokines but different Evasins have distinct selectivities for target chemokines.Structures, mutational experiments, and sequence comparisons are beginning to reveal the critical elements of Evasins for chemokine recognition.Evasins show efficacy in animal models of inflammatory diseases, suggesting that either natural Evasins or engineered variants have potential as therapeutic anti-inflammatory agents. Ticks are hematophagous arachnids that parasitize mammals and other hosts, feeding on their blood. Ticks secrete numerous salivary factors that enhance host blood flow or suppress the host inflammatory response. The recruitment of leukocytes, a hallmark of inflammation, is regulated by chemokines, which activate chemokine receptors on the leukocytes. Ticks target this process by secreting glycoproteins called Evasins, which bind to chemokines and prevent leukocyte recruitment. This review describes the recent discovery of numerous Evasins produced by ticks, their classification into two structural and functional classes, and the efficacy of Evasins in animal models of inflammatory diseases. The review also proposes a standard nomenclature system for Evasins and discusses the potential of repurposing or engineering Evasins as therapeutic anti-inflammatory agents. Ticks are hematophagous arachnids that parasitize mammals and other hosts, feeding on their blood. Ticks secrete numerous salivary factors that enhance host blood flow or suppress the host inflammatory response. The recruitment of leukocytes, a hallmark of inflammation, is regulated by chemokines, which activate chemokine receptors on the leukocytes. Ticks target this process by secreting glycoproteins called Evasins, which bind to chemokines and prevent leukocyte recruitment. This review describes the recent discovery of numerous Evasins produced by ticks, their classification into two structural and functional classes, and the efficacy of Evasins in animal models of inflammatory diseases. The review also proposes a standard nomenclature system for Evasins and discusses the potential of repurposing or engineering Evasins as therapeutic anti-inflammatory agents. Inflammation (see Glossary) is the complex physiological response to tissue injury or infection. A ubiquitous feature of inflamed tissues is the recruitment of leukocytes, which function to eliminate pathogens and repair tissue damage but can also perpetuate and amplify the response, leading to chronic inflammatory disease. Therefore, selective suppression of leukocyte recruitment is a potential approach to anti-inflammatory therapy. Leukocyte recruitment in inflammation is regulated by small proteins called chemokines, which are secreted at the site of injury or infection and then activate chemokine receptors expressed on the target leukocyte [1Murphy P.M. Chemokines and chemokine receptors.in: Rich R.R. Clinical Immunology E-Book: Principles and Practice. 5th edn. Elsevier Health Sciences, 2018: 157-170Google Scholar, 2Zlotnik A. Yoshie O. The chemokine superfamily revisited.Immunity. 2012; 36: 705-716Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar] (Box 1). Inhibition of chemokines or receptors could suppress recruitment of the leukocyte subsets expressing the relevant receptors without undesired inhibition of beneficial immune responses. However, effective targeting of specific responses is complicated by the complexity of the chemokine–receptor network, in which most receptors can be activated by several chemokines and most chemokines can activate more than one receptor. Therefore, it would be beneficial to identify or develop agents that can simultaneously target, for example, a group of chemokines that contribute to a particular inflammatory condition.Box 1Chemokines and Chemokine ReceptorsThe interactions of chemokines with chemokine receptors regulate the migration of leukocytes to sites of injury or infection and the homeostasis of leukocyte populations in bone marrow and lymphoid organs [60Fernandez E.J. Lolis E. Structure, function, and inhibition of chemokines.Annu. Rev. Pharmacol. Toxicol. 2002; 42: 469-499Crossref PubMed Scopus (494) Google Scholar, 61Moser B. et al.Chemokines: multiple levels of leukocyte migration control.Trends Immunol. 2004; 25: 75-84Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar]. They can also promote the migration of non-leukocyte cells in development and disease (e.g., cancer cells) and induce other cellular responses such as proliferation and differentiation [11Dimberg A. Chemokines in angiogenesis.Curr. Top. Microbiol. Immunol. 2010; 341: 59-80PubMed Google Scholar, 62Luther S.A. Cyster J.G. Chemokines as regulators of T cell differentiation.Nat. Immunol. 2001; 2: 102-107Crossref PubMed Scopus (585) Google Scholar]. Figure I shows the complex array of selectivity of human chemokines for human chemokine receptors and the expression of these receptors on different types of leukocytes.Humans express more than 40 chemokines and many additional gene variants, splice variants, and truncated or otherwise post-translationally modified forms (not shown) [63Stone M.J. et al.Mechanisms of regulation of the chemokine-receptor network.Int. J. Mol. Sci. 2017; 18: 342Crossref PubMed Scopus (143) Google Scholar]. Chemokines are classified, based on the spacing between the two N-terminal Cys residues, into two major families (CC and CXC) and two minor families (CX3CL and XCL) [2Zlotnik A. Yoshie O. The chemokine superfamily revisited.Immunity. 2012; 36: 705-716Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar, 64Zlotnik A. Yoshie O. Chemokines: a new classification system and their role in immunity.Immunity. 2000; 12: 121-127Abstract Full Text Full Text PDF PubMed Scopus (3232) Google Scholar]. For example, CCL1 is the systematic name for CC chemokine ligand-1, whose previous, nonsystematic name was I-309. CXC chemokines can be further subdivided based on the presence (ELR+) or absence (ELR-) of the Glu-Leu-Arg sequence, near the N terminus, as this sequence defines selectivity for the neutrophil receptors CXCR1 and CXCR2 [24Bachelerie F. et al.International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors.Pharmacol. Rev. 2014; 66: 1-79Crossref PubMed Scopus (548) Google Scholar]. Alternatively, chemokines can be categorized based on their homeostatic versus inflammatory functions [46Crump M.P. et al.Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1.EMBO J. 1997; 16: 6996-7007Crossref PubMed Scopus (625) Google Scholar].Chemokines collectively target 19 known members of the G protein-coupled receptor family, as well as genetic and splice variants and post-translationally modified forms [63Stone M.J. et al.Mechanisms of regulation of the chemokine-receptor network.Int. J. Mol. Sci. 2017; 18: 342Crossref PubMed Scopus (143) Google Scholar]. Chemokine receptors are classified based on the family of chemokines to which they predominantly bind (e.g., CXCR1 is CXC chemokine receptor-1) and are differentially expressed on various types of leukocytes [1Murphy P.M. Chemokines and chemokine receptors.in: Rich R.R. Clinical Immunology E-Book: Principles and Practice. 5th edn. Elsevier Health Sciences, 2018: 157-170Google Scholar]. In addition, there are also five atypical chemokine receptors (ACKRs), which are expressed on a variety of cell types [1Murphy P.M. Chemokines and chemokine receptors.in: Rich R.R. Clinical Immunology E-Book: Principles and Practice. 5th edn. Elsevier Health Sciences, 2018: 157-170Google Scholar] and are not G protein-coupled but respond to chemokines by recruitment of β-arrestins and internalization, thus removing chemokines from circulation. The interactions of chemokines with chemokine receptors regulate the migration of leukocytes to sites of injury or infection and the homeostasis of leukocyte populations in bone marrow and lymphoid organs [60Fernandez E.J. Lolis E. Structure, function, and inhibition of chemokines.Annu. Rev. Pharmacol. Toxicol. 2002; 42: 469-499Crossref PubMed Scopus (494) Google Scholar, 61Moser B. et al.Chemokines: multiple levels of leukocyte migration control.Trends Immunol. 2004; 25: 75-84Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar]. They can also promote the migration of non-leukocyte cells in development and disease (e.g., cancer cells) and induce other cellular responses such as proliferation and differentiation [11Dimberg A. Chemokines in angiogenesis.Curr. Top. Microbiol. Immunol. 2010; 341: 59-80PubMed Google Scholar, 62Luther S.A. Cyster J.G. Chemokines as regulators of T cell differentiation.Nat. Immunol. 2001; 2: 102-107Crossref PubMed Scopus (585) Google Scholar]. Figure I shows the complex array of selectivity of human chemokines for human chemokine receptors and the expression of these receptors on different types of leukocytes. Humans express more than 40 chemokines and many additional gene variants, splice variants, and truncated or otherwise post-translationally modified forms (not shown) [63Stone M.J. et al.Mechanisms of regulation of the chemokine-receptor network.Int. J. Mol. Sci. 2017; 18: 342Crossref PubMed Scopus (143) Google Scholar]. Chemokines are classified, based on the spacing between the two N-terminal Cys residues, into two major families (CC and CXC) and two minor families (CX3CL and XCL) [2Zlotnik A. Yoshie O. The chemokine superfamily revisited.Immunity. 2012; 36: 705-716Abstract Full Text Full Text PDF PubMed Scopus (695) Google Scholar, 64Zlotnik A. Yoshie O. Chemokines: a new classification system and their role in immunity.Immunity. 2000; 12: 121-127Abstract Full Text Full Text PDF PubMed Scopus (3232) Google Scholar]. For example, CCL1 is the systematic name for CC chemokine ligand-1, whose previous, nonsystematic name was I-309. CXC chemokines can be further subdivided based on the presence (ELR+) or absence (ELR-) of the Glu-Leu-Arg sequence, near the N terminus, as this sequence defines selectivity for the neutrophil receptors CXCR1 and CXCR2 [24Bachelerie F. et al.International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors.Pharmacol. Rev. 2014; 66: 1-79Crossref PubMed Scopus (548) Google Scholar]. Alternatively, chemokines can be categorized based on their homeostatic versus inflammatory functions [46Crump M.P. et al.Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1.EMBO J. 1997; 16: 6996-7007Crossref PubMed Scopus (625) Google Scholar]. Chemokines collectively target 19 known members of the G protein-coupled receptor family, as well as genetic and splice variants and post-translationally modified forms [63Stone M.J. et al.Mechanisms of regulation of the chemokine-receptor network.Int. J. Mol. Sci. 2017; 18: 342Crossref PubMed Scopus (143) Google Scholar]. Chemokine receptors are classified based on the family of chemokines to which they predominantly bind (e.g., CXCR1 is CXC chemokine receptor-1) and are differentially expressed on various types of leukocytes [1Murphy P.M. Chemokines and chemokine receptors.in: Rich R.R. Clinical Immunology E-Book: Principles and Practice. 5th edn. Elsevier Health Sciences, 2018: 157-170Google Scholar]. In addition, there are also five atypical chemokine receptors (ACKRs), which are expressed on a variety of cell types [1Murphy P.M. Chemokines and chemokine receptors.in: Rich R.R. Clinical Immunology E-Book: Principles and Practice. 5th edn. Elsevier Health Sciences, 2018: 157-170Google Scholar] and are not G protein-coupled but respond to chemokines by recruitment of β-arrestins and internalization, thus removing chemokines from circulation. Considering the roles of chemokines and chemokine receptors in responding to infection, it is understandable that various pathogens and disease vector organisms have evolved mechanisms for inhibiting host chemokines or receptors. These include viruses of the poxvirus and herpesvirus families [3Burns J.M. et al.Comprehensive mapping of poxvirus vCCI chemokine-binding protein: expanded range of ligand interactions and unusual dissociation kinetics.J. Biol. 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In addition, hard ticks, which are vectors for viral and bacterial pathogens, secrete proteins called Evasins, which bind to host chemokines, inhibiting their ability to activate chemokine receptors [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar, 9Frauenschuh A. et al.Molecular cloning and characterization of a highly selective chemokine-binding protein from the tick Rhipicephalus sanguineus.J. Biol. Chem. 2007; 282: 27250-27258Crossref PubMed Scopus (103) Google Scholar]. In the past few years, there has been substantial progress on characterizing these tick Evasins. There are several possible mechanisms by which chemokine inhibition by Evasins could be advantageous for ticks. Since one effect of inflammation is to make the host aware of the presence of the tick, suppressing inflammation may allow the tick to go undetected and therefore feed longer. In addition, Evasins are likely to reduce immunologically acquired host resistance, thereby increasing tick feeding and survival [10Wikel S.K. Host immunity to ticks.Annu. Rev. Entomol. 1996; 41: 1-22Crossref PubMed Scopus (211) Google Scholar]. Moreover, chemokines are also important for both angiogenesis [11Dimberg A. Chemokines in angiogenesis.Curr. Top. Microbiol. Immunol. 2010; 341: 59-80PubMed Google Scholar] and fibrotic cutaneous wound healing [12Ding J. Tredget E.E. The role of chemokines in fibrotic wound healing.Adv. Wound Care. 2015; 4: 673-686Crossref PubMed Google Scholar], both of which could be important in defense against ticks. In this review, we provide a comprehensive account of the current state of knowledge on tick Evasins. Specifically, we describe the initial discovery of Evasins in one tick species, experiments exploring their efficacy in animal models of inflammatory disease, and the subsequent identification of hundreds of potential Evasins from numerous tick species. We describe the classification of Evasins into two protein families and insights into the structural basis of their chemokine recognition and inhibition. To assist future research in this area, we propose a unified nomenclature for tick Evasins. Finally, we discuss the potential of Evasins as clinically useful anti-inflammatory agents. Hematophagous organisms, such as ticks, obtain their nourishment from the blood of their hosts. To do so, they have developed an armory of molecules including anticoagulants, analgesics, and anti-inflammatory molecules that allow them to remain undetected on the host while obtaining their blood feed, sometimes for as long as 2–3 weeks [13Ribeiro J.M. Blood-feeding arthropods: live syringes or invertebrate pharmacologists?.Infect. Agents Dis. 1995; 4: 143-152PubMed Google Scholar, 14Ribeiro J.M. et al.Antihemostatic, antiinflammatory, and immunosuppressive properties of the saliva of a tick, Ixodes dammini.J. Exp. Med. 1985; 161: 332-344Crossref PubMed Scopus (302) Google Scholar, 15Brossard M. Wikel S.K. Tick immunobiology.Parasitology. 2004; 129: S161-S176Crossref PubMed Scopus (197) Google Scholar, 16Kotal J. et al.Modulation of host immunity by tick saliva.J. Proteomics. 2015; 128: 58-68Crossref PubMed Scopus (123) Google Scholar, 17Kazimirova M. Stibraniova I. Tick salivary compounds: their role in modulation of host defences and pathogen transmission.Front. Cell. Infect. Microbiol. 2013; 3: 43Crossref PubMed Scopus (215) Google Scholar]. The first evidence of antichemokine activity in ticks came from the observation that salivary gland extracts from several ixodid tick species could neutralize activity of the chemokine CXCL8 [18Hajnicka V. et al.Anti-interleukin-8 activity of tick salivary gland extracts.Parasite Immunol. 2001; 23: 483-489Crossref PubMed Scopus (78) Google Scholar, 19Kocakova P. et al.Effect of fast protein liquid chromatography fractionated salivary gland extracts from different ixodid tick species on interleukin-8 binding to its cell receptors.Folia Parasitol. 2003; 50: 79-84Crossref PubMed Scopus (17) Google Scholar]. The same group then showed that tick saliva contains inhibitory activities directed against the chemokines CCL2, CCL3, CCL5, and CCL11 [20Hajnicka V. et al.Manipulation of host cytokine network by ticks: a potential gateway for pathogen transmission.Parasitology. 2005; 130: 333-342Crossref PubMed Scopus (65) Google Scholar]. Importantly, mRNA levels for several of these chemokines are elevated in human skin biopsies from tick bites compared with unaffected skin [21Glatz M. et al.Characterization of the early local immune response to Ixodes ricinus tick bites in human skin.Exp. Dermatol. 2017; 26: 263-269Crossref PubMed Scopus (24) Google Scholar], suggesting that these chemokines are involved in the human reaction to tick bites. Evidence that the chemokine inhibitory activity was due to discrete molecules was first provided by two experimental approaches in the Proudfoot laboratory: SDS-PAGE analysis of the saliva from the hard tick species R. sanguineus (common brown dog tick) following crosslinking to radiolabeled chemokine [9Frauenschuh A. et al.Molecular cloning and characterization of a highly selective chemokine-binding protein from the tick Rhipicephalus sanguineus.J. Biol. Chem. 2007; 282: 27250-27258Crossref PubMed Scopus (103) Google Scholar]; and isolation from the saliva by protein chip affinity followed by mass spectrometric analysis [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar]. Molecular identification of these chemokine-binding proteins by expression cloning yielded three novel proteins named Evasin-1, -3, and -4 [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar, 9Frauenschuh A. et al.Molecular cloning and characterization of a highly selective chemokine-binding protein from the tick Rhipicephalus sanguineus.J. Biol. Chem. 2007; 282: 27250-27258Crossref PubMed Scopus (103) Google Scholar]. Although the predicted molecular masses of the encoded proteins were 10.5, 7.0, and 12.0 kDa, respectively, these proteins appeared as broad bands of around 30 kDa (Evasin-1 and -3) and 50 kDa (Evasin-4) in the supernatants from HEK293 cells transfected with the tick salivary gland cDNA library, because they are all heavily glycosylated. Glycosylation may be an important feature to protect the proteins from proteolytic cleavage and immune recognition and thus extend their half-life while the ticks carry out their blood feeds. However, expression of recombinant Evasins has shown that the activity of unglycosylated Evasins was equivalent to the glycosylated forms, indicating that glycosylation is not a prerequisite for chemokine binding and inhibition in vitro [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar, 9Frauenschuh A. et al.Molecular cloning and characterization of a highly selective chemokine-binding protein from the tick Rhipicephalus sanguineus.J. Biol. Chem. 2007; 282: 27250-27258Crossref PubMed Scopus (103) Google Scholar, 22Hayward J. et al.Ticks from diverse genera encode chemokine-inhibitory evasin proteins.J. Biol. Chem. 2017; 292: 15670-15680Crossref PubMed Scopus (34) Google Scholar]. Determination of their chemokine selectivity profiles suggested that there were at least two classes of Evasins. Evasin-1 was rather selective, binding to several CC chemokines – CCL3, CCL3L1, CCL4, CCL4L1, CCL14, and CCL18. Evasin-4 also bound only CC chemokines but was less selective, binding around 20 CC chemokines [23Déruaz M. et al.Evasin-4, a tick-derived chemokine-binding protein with broad selectivity can be modified for use in preclinical disease models.FEBS J. 2013; 280: 4876-4887Crossref PubMed Scopus (31) Google Scholar], although not the monocyte chemoattractants CCL2 or CCL13. However, Evasin-3 bound and inhibited several ELR+ CXC chemokines (Box 1) but not CC chemokines [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar, 24Bachelerie F. et al.International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors.Pharmacol. Rev. 2014; 66: 1-79Crossref PubMed Scopus (548) Google Scholar]. The antichemokine selectivity of Evasins has been tested mostly on human chemokines due to their availability. However, ticks may feed on several different host species, including humans and rodents. The three Evasins identified from R. sanguineus inhibit murine as well as human chemokines, as demonstrated in the disease models described below [9Frauenschuh A. et al.Molecular cloning and characterization of a highly selective chemokine-binding protein from the tick Rhipicephalus sanguineus.J. Biol. Chem. 2007; 282: 27250-27258Crossref PubMed Scopus (103) Google Scholar], and there is a good correspondence between the selectivity of Evasins for human and mouse chemokines [25Singh K. et al.Yeast surface display identifies a family of evasins from ticks with novel polyvalent CC chemokine-binding activities.Sci. Rep. 2017; 7: 4267Crossref PubMed Scopus (22) Google Scholar]. However, their selectivity for chemokines from other species remains to be thoroughly explored. Evasins -1, -3, and -4 have all been expressed recombinantly in Escherichia coli and/or mammalian cells, enabling evaluation of their therapeutic potential in inflammatory disease models. Evasin-1 reduced neutrophil recruitment induced by CCL3 in a murine peritoneal cell recruitment assay, consistent with the expression of CCR1, a receptor for CCL3, on mouse neutrophils [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar]. Similarly, in a mouse model of lung fibrosis induced by administration of bleomycin, Evasin -1 had protective effects and reduced mortality through inhibition of neutrophil infiltration [26Russo R.C. et al.Therapeutic effects of evasin-1, a chemokine binding protein, in bleomycin-induced pulmonary fibrosis.Am. J. Respir. Cell Mol. Biol. 2011; 45: 72-80Crossref PubMed Scopus (45) Google Scholar]. Evasin-1 also reversed the skin inflammation observed in D6–/– mice in response to 12-O-tetradecanoylphorbol-13-acetate [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar], a model previously shown to depend on several inflammatory chemokines [27Jamieson T. et al.The chemokine receptor D6 limits the inflammatory response in vivo.Nat. Immunol. 2005; 6: 403-411Crossref PubMed Scopus (250) Google Scholar], suggesting that CCL3 may be a key player in this model. Unfortunately, translation of these results to humans is not straightforward because the cognate receptors for CCL3 (CCR1 and CCR5) are not normally expressed on human neutrophils. Evasin-3 was also effective in several murine neutrophil-dependent disease models, as expected from its in vitro selectivity profile showing that it inhibits ELR+ chemokines that activate the receptor CXCR2, which is expressed on neutrophils. Evasin-3 inhibited leukocyte infiltration into the peritoneal cavity in response to CXCL1 [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar]. Similarly, Evasin-3 significantly decreased symptoms of antigen-induced arthritis induced by intradermal administration of bovine serum albumin, a highly neutrophil-dependent model [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar]. In ischemic reperfusion injury, another neutrophil-mediated model, both Evasin-1 and -3 were protective but Evasin-3 appeared to be more efficacious [8Deruaz M. et al.Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.J. Exp. Med. 2008; 205: 2019-2031Crossref PubMed Scopus (171) Google Scholar], indicating that the CXCR2 ligands play a predominant role in this model. In contrast, only Evasin-1 and not Evasin-3 was effective in inhibiting the first wave of dendritic cell recruitment to the site of infection with Leishmania major, since it is mediated by neutrophil-secreted CCL3 [28Charmoy M. et al.Neutrophil-derived CCL3 is essential for the rapid recruitment of dendritic cells to the site of Leishmania major inoculation in resistant mice.PLoS Pathog. 2010; 6: e1000755Crossref PubMed Scopus (115) Google Scholar]. In line with its broad selectivity profile and inhibitory activity against proinflammatory CC chemokines, Evasin-4 has also been shown to be protective in a number of mouse models, including dextran sulfate-induced colitis [29Braunersreuther V. et al.Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice.Thromb. Haemost. 2013; 110: 807-825Crossref PubMed Scopus (43) Google Scholar, 30Vieira A.T. et al.Treatment with a novel chemokine-binding protein or eosinophil lineage-ablation protects mice from experimental colitis.Am. J. Pathol. 2009; 175: 2382-2391Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar] and postinfarction myocardial injury and remodeling following left coronary artery permanent ligature [31Bonvin P. et al.Identification of the pharmacophore of the CC chemokine-binding proteins Evasin-1 and -4 using phage display.J. Biol. Chem. 2014; 289: 31846-31855Crossref PubMed Scopus (19) Google Scholar]. In the latter model, treatment with both Evasin-3 and -4 was associated with beneficial reduction in infarct size and decreases in leukocyte infiltration, reactive oxygen species (ROS) release, and circulating levels of CXCL1 and CCL2. Evasin-4 induced a more potent effect, abrogating the inflammation already observed 1 day after ischemia onset. Although both Evasins failed to significantly improve cardiac function, remodeling, and scar formation, selective inhibition of CC chemokines with Evasin-4 reduced cardiac injury and inflammation and improved survival. Evasin-3 and -4 have also been compared in a mouse model of acute pancreatitis (and associated lung inflammation) induced by cerulean [32Montecucco F. et al.Treatment with Evasin-3 abrogates neutrophil-mediated inflammation in mouse acute pancreatitis.Eur. J. Clin. Invest. 2014; 44: 940-950Crossref PubMed Scopus (33) Google Scholar]. Treatment with Evasin-3 decreased neutrophil infiltration, ROS production, and apoptosis in the lung, and reduced neutrophils, macrophage apoptosis, and necrosis in the pancreas. Evasin-4, however, only reduced macrophage content in the lung and did not provide any benefit at pancreas level. Taken together, the results using these animal models show that Evasins may have therapeutic potential in a variety of inflammatory disease settings but also highlight some of the limitations and pot
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