Phylogenetic Analysis Indicates That Evasin-Like Proteins of Ixodid Ticks Fall Into Three Distinct Classes.

Chemokines are structurally related proteins that activate leucocyte migration in response to injury or infection. Tick saliva contains chemokine-binding proteins or evasins which likely neutralize host chemokine function and inflammation. Biochemical characterisation of 50 evasins from Ixodes, Amblyomma and Rhipicephalus shows that they fall into two functional classes, A and B, with exclusive binding to either CC- or CXC- chemokines, respectively. Class A evasins, EVA1 and EVA4 have a four-disulfide-bonded core, whereas the class B evasin EVA3 has a three-disulfide-bonded "knottin" structure. All 29 class B evasins have six cysteine residues conserved with EVA3, arrangement of which defines a Cys6-motif. Nineteen of 21 class A evasins have eight cysteine residues conserved with EVA1/EVA4, the arrangement of which defines a Cys8-motif. Two class A evasins from Ixodes (IRI01, IHO01) have less than eight cysteines. Many evasin-like proteins have been identified in tick salivary transcriptomes, but their phylogenetic relationship with respect to biochemically characterized evasins is not clear. Here, using BLAST searches of tick transcriptomes with biochemically characterized evasins, we identify 292 class A and 157 class B evasins and evasin-like proteins from Prostriate (Ixodes), and Metastriate (Amblyomma, Dermacentor, Hyalomma, Rhipicephalus) ticks. Phylogenetic analysis shows that class A evasins/evasin-like proteins segregate into two classes, A1 and A2. Class A1 members are exclusive to Metastriate ticks and typically have a Cys8-motif and include EVA1 and EVA4. Class A2 members are exclusive to Prostriate ticks, lack the Cys8-motif, and include IHO01 and IRI01. Class B evasins/evasin-like proteins are present in both Prostriate and Metastriate lineages, typically have a Cys6-motif, and include EVA3. Most evasins/evasin-like proteins in Metastriate ticks belong to class A1, whereas in Prostriate species they are predominantly class B. In keeping with this, the majority of biochemically characterized Metastriate evasins bind CC-chemokines, whereas the majority of Prostriate evasins bind CXC-chemokines. While the origin of the structurally dissimilar classes A1 and A2 is yet unresolved, these results suggest that class B evasin-like proteins arose before the divergence of Prostriate and Metastriate lineages and likely functioned to neutralize CXC-chemokines and support blood feeding.

Chemokines encoded by herpesviruses.

Viruses use diverse strategies to elude the immune system, including copying and repurposing host cytokine and cytokine receptor genes. For herpesviruses, the chemokine system of chemotactic cytokines and receptors is a common source of copied genes. Here, we review the current state of knowledge about herpesvirus-encoded chemokines and discuss their possible roles in viral pathogenesis, as well as their clinical potential as novel anti-inflammatory agents or targets for new antiviral strategies.

Overview and potential unifying themes of the atypical chemokine receptor family.

Chemokines modulate immune responses through their ability to orchestrate the migration of target cells. Chemokines directly induce cell migration through a distinct set of 7 transmembrane domain G protein-coupled receptors but are also recognized by a small subfamily of atypical chemokine receptors, characterized by their inability to support chemotactic activity. Atypical chemokine receptors are now emerging as crucial regulatory components of chemokine networks in a wide range of physiologic and pathologic contexts. Although a new nomenclature has been approved recently to reflect their functional distinction from their conventional counterparts, a systematic view of this subfamily is still missing. This review discusses their biochemical and immunologic properties to identify potential unifying themes in this emerging family.

An atypical addition to the chemokine receptor nomenclature: IUPHAR Review 15.

Chemokines and their receptors are essential regulators of in vivo leukocyte migration and, some years ago, a systematic nomenclature system was developed for the chemokine receptor family. Chemokine receptor biology and biochemistry was recently extensively reviewed. In this review, we also highlighted a new component to the nomenclature system that incorporates receptors previously known as 'scavenging', or 'decoy', chemokine receptors on the basis of their lack of classical signalling responses to ligand binding and their general ability to scavenge, or sequester, their cognate chemokine ligands. These molecules are now collectively referred to as 'atypical chemokine receptors', or ACKRs, and play fundamental roles in regulating in vivo responses to chemokines. This commentary highlights this new addition to the chemokine receptor nomenclature system and provides brief information on the four receptors currently covered by this nomenclature.

Regulation of atherosclerotic plaque inflammation.

The immune reactions that regulate atherosclerotic plaque inflammation involve chemokines, lipid mediators and costimulatory molecules. Chemokines are a family of chemotactic cytokines that mediate immune cell recruitment and control cell homeostasis and activation of different immune cell types and subsets. Chemokine production and activation of chemokine receptors form a positive feedback mechanism to recruit monocytes, neutrophils and lymphocytes into the atherosclerotic plaque. In addition, chemokine signalling affects immune cell mobilization from the bone marrow. Targeting several of the chemokines and/or chemokine receptors reduces experimental atherosclerosis, whereas specific chemokine pathways appear to be involved in plaque regression. Leukotrienes are lipid mediators that are formed locally in atherosclerotic lesions from arachidonic acid. Leukotrienes mediate immune cell recruitment and activation within the plaque as well as smooth muscle cell proliferation and endothelial dysfunction. Antileukotrienes decrease experimental atherosclerosis, and recent observational data suggest beneficial clinical effects of leukotriene receptor antagonism in cardiovascular disease prevention. By contrast, other lipid mediators, such as lipoxins and metabolites of omega-3 fatty acids, have been associated with the resolution of inflammation. Costimulatory molecules play a central role in fine-tuning immunological reactions and mediate crosstalk between innate and adaptive immunity in atherosclerosis. Targeting these interactions is a promising approach for the treatment of atherosclerosis, but immunological side effects are still a concern. In summary, targeting chemokines, leukotriene receptors and costimulatory molecules could represent potential therapeutic strategies to control atherosclerotic plaque inflammation.

Functional roles of evolutionary conserved motifs and residues in vertebrate chemokine receptors.

Chemokine receptors regulate cell migration and homing. They belong to the rhodopsin-like family of GPCRs. Their ancestor genes emerged in the early stages of vertebrate evolution. Since then, the family has been greatly expanded through whole and segmental genome duplication events. During evolution, many amino acid changes have been introduced in individual chemokine receptors, but certain motifs and residues are highly conserved. Previously, we proposed a nomenclature system of the vertebrate chemokine receptors based on their evolutionary history and phylogenetic analyses. With the use of this classification system, we are now able to confidently assign the species orthologs of vertebrate chemokine receptors. Here, we systematically analyze conserved motifs and residues of each group of orthologous chemokine receptors that may play important roles in their signaling and biologic functions. Our present analysis may provide useful information on how individual chemokine receptors are activated upon ligand binding.

Chemokine receptors in Atlantic salmon.

Teleost sequence data have revealed that many immune genes have evolved differently when compared to other vertebrates. Thus, each gene family needs functional studies to define the biological role of individual members within major species groups. Chemokine receptors, being excellent markers for various leukocyte subpopulations, are one such example where studies are needed to decipher individual gene function. The unique salmonid whole genome duplication that occurred approximately 95 million years ago has provided salmonids with many additional duplicates further adding to the complexity and diversity. Here we have performed a systematic study of these receptors in Atlantic salmon with particular focus on potential inflammatory receptors. Using the preliminary salmon genome data we identified 48 chemokine or chemokine-like receptors including orthologues to the ten receptors previously published in trout. We found expressed support for 40 of the bona fide salmon receptors. Eighteen of the chemokine receptors are duplicated, and when tested against a diploid sister group the majority were shown to be remnants of the 4R whole genome duplication with subsequent high sequence identity. The salmon chemokine receptor repertoire of 40 expressed bona fide genes is comparably larger than that found in humans with 23 receptors. Diversification has been a major driving force for these duplicate genes with the main variability residing in ligand binding and signalling domains.

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.

Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145-176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and soluble chemokine-binding proteins have been described. Here, we review this extended family of chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical chemokine receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human Genome Nomenclature Committee.

A beginner's guide to chemokines.

This review provides an overview of chemokines and their receptors, with an emphasis on general features and nomenclature along with a short summary of their properties and functions. It is intended as an introduction to the subject and a reference point for those wishing to learn key facts about chemokines and their role in biology.

A family tree of vertebrate chemokine receptors for a unified nomenclature.

Chemokines receptors are involved in the recruitment of various cell types in inflammatory and physiological conditions. There are 23 known chemokine receptor genes in the human genome. However, it is still unclear how many chemokine receptors exist in the genomes of various vertebrate species other than human and mouse. Moreover, the orthologous relationships are often obscure between the genes of higher and lower vertebrates. In order to provide a basis for a unified nomenclature system of the vertebrate chemokine receptor gene family, we have analysed the chemokine receptor genes from the genomes of 16 vertebrate species, and classify them into 29 orthologous groups using phylogenetic and comparative genomic analyses. The results reveal a continuous gene birth and death process during the vertebrate evolution and an interesting evolutionary history of the chemokine receptor genes after the emergence in agnathans.

Increased type 1 chemokine expression in experimental Chagas disease correlates with cardiac pathology in beagle dogs.

Chemokines and chemokine receptors interaction have presented important role in leukocyte migration to specific immune reaction sites. Recently, it has been reported that chemokine receptors CXC (CXCR3) and CC (CCR5) were preferentially expressed on Th1 cells while CCR3 and CCR4 were preferentially expressed on Th2 cells. This study evaluated the mRNA expression of type 1 and type 2 chemokine and chemokine receptors in the cardiac tissue of Beagle dogs infected with distinct genetic groups of Trypanosoma cruzi (Y, Berenice-78 and ABC strains) during acute and chronic phases. To analyze the correlation between chemokine and chemokine receptors expression and the development of heart pathology, the chronic infected animals were divided into groups, according to the parasite strain and based on the degree of heart damage: cardiac and indeterminate form of Chagas disease. Our results indicated that cardiac type1/2 chemokines and their receptors were partially dependent on the genetic diversity of parasites as well as the polarization of clinical forms. Also, dogs presenting cardiac form showed lower heart tissue mRNA expression of CCL24 (type 2) and higher expression of CCL5, CCL4 and CXCR3 (type 1) when compared with those with indeterminate form of disease. Together, these data reinforce a close-relation between T. cruzi genetic population and the host specific type 1 immune response and, for the first time, we show the distribution of type 1/2 chemokines associated with the development of cardiac pathology using dogs, a well similar model to study human Chagas disease.

Cloning of porcine chemerin, ChemR23 and GPR1 and their involvement in regulation of lipogenesis.

Chemerin is a novel adipokine which is abundant in adipose tissue to promote adipocyte differentiation and with significant relativity to BMI and insulin sensitivity. We report here the molecular characterization of porcine chemerin and its receptors ChemR23 and GPR1, as well as their transcriptional regulation during lipogenesis. Chemerin was mainly expressed in liver, intestine, kidney and adipose tissue, consistent with the expression pattern of GPR1, but not ChemR23, which was predominantly present in spleen and temperately in adipose tissue. We further investigated the lipogenesis-related transcriptional activation of PPAR/ and KLF15 on chemerin and its receptors. The data showed that KLF15, but not PPAR/, can up-regulate the mRNA level of chemerin, ChemR23 and GPR1, which was consistent with the results of luciferase assay that confirmed the effect of KLF15 on ChemR23 promoter. Taken together, our data provide basic molecular information for the further investigation on the function of chemerin in lipogenesis.

Chemokine expression in the white matter spinal cord precursor niche after force-defined spinal cord contusion injuries in adult rats.

Inflammatory cascades induced by spinal cord injuries (SCI) are localized in the white matter, a recognized neural stem- and progenitor-cell (NSPC) niche of the adult spinal cord. Chemokines, as integrators of these processes, might also be important determinants of this NSPC niche. CCL3/CCR1, CCL2/CCR2, and SDF-1alpha/CXCR4 were analyzed in the ventrolateral white matter after force defined thoracic SCI: Immunoreactivity (IR) density levels were measured 2 d, 7 d, 14 d, and 42 d on cervical (C 5), thoracic (T 5), and lumbar (L 5) levels. On day post operation (DPO) 42, chemokine inductions were further evaluated by real-time RT-PCR and Western blot analyses. Cellular phenotypes were confirmed by double labeling with markers for major cell types and NSPCs (nestin, Musashi-1, NG2, 3CB2, BLBP). Mitotic profiles were investigated in parallel by BrdU labeling. After lesion, chemokines were induced in the ventrolateral white matter on IR-, mRNA-, and protein-level. IR was generally more pronounced after severe lesions, with soaring increases of CCL2/CCR2 and continuous elevations of CCL3/CCR1. SDF-1alpha and CXCR4 IR induction was focused on thoracic levels. Chemokines/-receptors were co-expressed with astroglial, oligodendroglial markers, nestin, 3CB2 and BLBP by cells morphologically resembling radial glia on DPO 7 to DPO 42, and NG2 or Musashi-1 on DPO 2 and 7. In the white matter BrdU positive cells were significantly elevated after lesion compared with sham controls on all investigated time points peaking in the early time course on thoracic level: Here, chemokines were co-expressed by subsets of BrdU-labeled cells. These findings suggest an important role of chemokines/-receptors in the subpial white matter NSPC niche after SCI.

Prediction and classification of chemokines and their receptors.

Chemokines are low molecular mass cytokine-like proteins that orchestrate myriads of immune functions like leukocyte trafficking, T cell differentiation, angiogenesis, hematopeosis and mast cell degranulation. Chemokines also play a role as HIV-1 inhibitor and act as potent natural adjuvant in antitumor immunotherapy. Receptors for these molecules are all seven-pass transmembrane G-protein-coupled receptors that are intimately involved with chemokines in a wide array of physiological and pathological conditions. These receptors also have a major role as co-receptors for HIV-1 entry into target cells. Therefore, chemokine receptors have proven to be excellent targets for small molecule in pharmaceutical industry. The immense importance of chemokines and their receptors motivated us to develop a support vector machine-based method ChemoPred to predict this important class of proteins and further classify them into subfamilies. ChemoPred is capable of predicting chemokines and chemokine receptors with an accuracy of 95.08% and 92.19%, respectively. The overall accuracy of classification of chemokines into three subfamilies was 96.00% and that of chemokine receptors into three families was 92.87%. The server ChemoPred is freely available at www.imtech.res.in/raghava/chemopred.

Non-signaling chemokine receptors: mechanism of action and role in vivo.

Cell migration is fundamental for numerous biological processes and is critical for the pathogenesis of several diseases. Chemokines represent the main class of mediators providing cell directional migration and several levels of regulation of their function have been identified. A subfamily of chemokine receptors not able to transduce chemotactic signals plays an important role in the control of chemokine concentrations through binding, internalization and degradation of chemotactic factors. Here we review in vitro and in vivo evidences indicating that these 'silent' chemokine receptors represent a strategy to regulate innate and adaptive immunity.

[Chemokines: a sophisticated cell-guidance network]. / Les chimiokines: un réseau sophistiqué de guidage cellulaire.

The immune system relies on the motility on various cell types that roam the host through the blood, the peripheral tissues and the lymphoid organs, looking for pathogens. Along their maturation and/or activation, the cell migratory capacities change in order to allow them to leave organs where they have been produced such as thymus and bone marrow, to locate in strategic sites to sense surrounding microbes, to meet and interact with other cells, and finally to access peripheral tissues and organs to eradicate the pathogens. This cell traffic is a highly organized process that involves numerous protein families such as adhesion molecules, proteases and chemotactic factors. Among the latter, chemokines are in the front line. We will here summarize the recent findings stressing out their physiopathological relevance and will describe thereafter their possible therapeutic use.

Quantification of chemokines by real-time reverse transcriptase PCR: applications in type 1 diabetes.

Type 1 diabetes is a T-cell mediated autoimmune disease, characterized by the destruction of insulin-producing pancreatic beta-cells. This review will discuss the role of chemokines in the recruitment of immune cells leading to the pathology of this disease. There will be a focus on the quantification of chemokines and chemokine receptors by the recently developed real-time reverse transcriptase PCR technique. Today, this technique is in widespread use for analysis of chemokines in cells, tissues and tissue biopsies. The minute amount of tissue needed for analysis, as well as the very high sensitivity of this method, make it the method of choice for analysis of chemokines, which are often expressed at very low levels in target tissues. However, validation and optimization of the technique is of crucial importance for obtaining reliable results.