The role of chemokines in the recruitment of lymphocytes to the liver

Chemokines direct leukocyte trafficking and positioning within tissues. They thus play critical roles in regulating immune responses and inflammation. The chemokine system is complex involving interactions between multiple chemokines and their receptors that operate in combinatorial cascades with adhesion molecules. The involvement of multiple chemokines and chemokine receptors in these processes brings flexibility and specificity to recruitment. The hepatic vascular bed is a unique low flow environment through which leukocyte are recruited to the liver during homeostatic immune surveillance and in response to infection or injury. The rate of leukocyte recruitment and the nature of cells recruited through the sinusoids in response to inflammatory signals will shape the severity of disease. At one end of the spectrum fulminant liver failure results from a rapid recruitment of leukocytes that leads to hepatocyte destruction and liver failure at the other diseases such as chronic hepatitis C infection may progress over many years from hepatitis to fibrosis and cirrhosis. Chronic hepatitis is charactezised by a T lymphocyte rich infiltrate and the nature and outcome of hepatitis will depend on the T cell subsets recruited, their activation and function within the liver. Different subsets of effector T cells have been described based on their secretion of cytokines and specific functions. These include Th1 and Th2 cells and more recently Th17 and Th9 cells which are associated with different types of immune response and which express distinct patterns of chemokine receptors that promote their recruitment under particular conditions. The effector function of these cells is balanced by the recruitment of regulatory T cells that are able to suppress antigen-specific effectors to allow resolution of immune responses and restoration of immune homeostasis. Understanding the signals that are responsible for recruiting different lymphocyte subsets to the liver will elucidate disease pathogenesis and open up new therapeutic approaches to modulate recruitment in favour of resolution rather than injury.     

Chemokine and chemokine receptors in autoimmunity: the case of primary biliary cholangitis

Chemokines represent a major mediator of innate immunity and play a key role in the selective recruitment of cells during localized inflammatory responses. Beyond critical extracellular mediators of leukocyte trafficking, chemokines and their cognate receptors are expressed by a variety of resident and infiltrating cells (monocytes, lymphocytes, NK cells, mast cells, and NKT cells). Chemokines represent ideal candidates for mechanistic studies (particularly in murine models) to better understand the pathogenesis of chronic inflammation and possibly become biomarkers of disease. Nonetheless, therapeutic approaches targeting chemokines have led to unsatisfactory results in rheumatoid arthritis, while biologics against pro-inflammatory cytokines are being used worldwide with success. In this comprehensive review we will discuss the evidence supporting the involvement of chemokines and their specific receptors in mediating the effector cell response, utilizing the autoimmune/primary biliary cholangitis setting as a paradigm.     

The role of chemokines in the pathogenesis of neurotropic flaviviruses

Neurotropic flaviviruses are important emerging and reemerging arthropod-borne pathogens that cause significant morbidity and mortality in humans and other vertebrates worldwide. Upon entry and infection of the CNS, these viruses can induce a rapid inflammatory response characterized by the infiltration of leukocytes into the brain parenchyma. Chemokines and their receptors are involved in coordinating complex leukocyte trafficking patterns that regulate viral pathogenesis in vivo. In this review, we will summarize the current literature on the role of chemokines in regulating the pathogenesis of West Nile, Japanese encephalitis, and tick-borne encephalitis virus infections in mouse models and humans. Understanding how viral infections trigger chemokines, the key cellular events that occur during the infection process, as well as the immunopathogenic role of these cells, are critical areas of research that may ultimately guide a much needed effort toward developing specific immunomodulators and/or antiviral therapeutics.     

Chemokines, mononuclear cells and the nervous system: heaven (or hell) is in the details

Chemokines and their receptors are essential elements in leukocyte trafficking during health and disease. There are three (or more) distinct routes of leukocyte entry into the central nervous system (CNS), and molecular mechanisms of physiological and neuroinflammatory leukocyte recruitment to the CNS are slowly coming into view. Migration of immune cells into cerebrospinal fluid supports CNS immunosurveillance. Current knowledge of the trafficking determinants that direct the leukocyte recruitment in CNS pathology relies in large part on studies of multiple sclerosis and its models including experimental autoimmune encephalomyelitis. Overlapping molecular signals are responsible for the migration of specific cells into the CNS during pathological inflammation and host defense, raising challenges and opportunities for therapeutic manipulation.     

Chemokines: directing leukocyte infiltration into allografts

Chemokines have been shown to play a critical role in the recruitment of leukocytes to transplanted organs. Animal models and clinical studies have demonstrated predictable temporal and spatial correlations between chemokine production and leukocyte infiltration into allografts. Antagonism of chemokines or chemokine receptors has been shown to delay leukocyte infiltration and prolong graft function, demonstrating an important role for chemokines in allograft rejection.     

Analysis of homing receptor expression on infiltrating leukocytes in disease states

Chemokines represent a large family of polypeptides that signal through G-protein-coupled receptors and have a role in chemotaxis, leukocyte homing, inflammation, hematopoiesis, angiogenesis and tumor growth. The chemokine/chemokine receptor system acts in coordination with a complex cytokine network to elicit and direct leukocyte infiltration into the inflamed tissue. In addition to promoting movement into the inflamed tissue, the chemokine/chemokine receptor system may also activate infiltrating cells, such as neutrophils and eosinophils, and induce local damage. In recent years, the elucidation of intricate chemokine networks has led to the identification of potential target molecules for therapeutic intervention. Of considerable interest has been the role of chemokine/chemokine receptors in regulating allergic lung inflammation. In this review, techniques to study in situ expression of chemokine receptors in inflamed tissues are presented and discussed.     

Chemokines and leukocyte trafficking in rheumatoid arthritis.

Leukocyte infiltration into the joint space and tissues is an essential component of the pathogenesis of rheumatoid arthritis (RA). In this review, we will summarize the current understanding of the mechanisms of leukocyte trafficking into the synovium, focusing on the role of adhesion molecules, chemokines, and chemokine receptors in synovial autoimmune inflammation. The process by which a circulating leukocyte decides to migrate into the synovium is highly regulated and involves the capture, firm adhesion, and transmigration of cells across the endothelial monolayer. Adhesion molecules and chemokine signals function in concert to mediate this process and to organize leukocytes into distinct structures within the synovium. Chemokines play a key regulatory role in organ-specific leukocyte trafficking and activation by affecting integrin activation, chemotaxis, effector cell function, and cell survival. Consequently, chemokines, their receptors, and downstream signal transduction molecules are attractive therapeutic targets for RA.     

Targeting the chemokine network in renal inflammation

Chemokines and their receptors are involved in the pathogenesis of renal diseases. They mediate leukocyte recruitment and activation during initiation as well as progression of renal inflammation. Infiltrating leukocyte subpopulations contribute to renal damage by releasing inflammatory and profibrotic cytokines. All intrinsic renal cells are capable of chemokine secretion on stimulation in vitro. Expression of inflammatory chemokines correlates with renal damage and local accumulation of chemokine receptor-bearing leukocytes in a variety of animal models of renal diseases as well as in human biopsy studies. Chemokines and their respective receptors could represent new targets for therapeutic intervention in renal inflammatory disease states that often tend to progress to end-stage renal disease. This article summarizes the present data on the role of chemokines and their receptors in renal inflammation with special emphasis on our efforts to identify the chemokine receptors CCR1 and CCR2 as promising targets for therapeutic intervention.     

An apparent paradox: chemokine receptor agonists can be used for anti-inflammatory therapy

Inflammation plays an important role in a wide range of human diseases. Chemokines are a group of proteins which control the migration and activation of the immune cells involved in all aspects of the inflammatory response. Chemokines bind to specific receptors of the seven-transmembrane spanning type on target leukocytes and also bind to cell-surface glycosaminoglycans (GAG). Leukocytes express a range of chemokine receptors which can cross-desensitise each other, potentially allowing a single chemokine receptor agonist to desensitise all the chemokine receptors on a cell. If an appropriate single receptor agonist is engineered to be non-chemotactic itself, then a treated cell will lose the potential to migrate in response to chemokines towards any developing site of inflammation. A non-GAG-binding but receptor agonistic form of the chemokine CCL7 can inhibit leukocyte recruitment in response to a diverse range of chemokines in vitro and in vivo. We hypothesise that this modified chemokine mediates its effect by inducing homologous and heterologous receptor desensitisation and further propose that other suitable candidates could include agonistic chemokine receptor-specific antibodies or small molecule chemokine receptor agonists. Hence, an appropriate chemokine receptor agonist could be used to inhibit multiple chemokine receptors, thereby producing a powerful and robust anti-inflammatory effect. This review considers the mechanisms leading to chemokine receptor desensitisation and discusses the potential to develop a new class of anti-inflammatory agents based on targeted stimulation of chemokine receptors.     

Chemokines and Chemokine Receptors： Their Manifold Roles in Homeostasis and Disease

Chemokines are a superfamily of small proteins that bind to G protein-coupled receptors on target cells and were originally discovered as mediators of directional migration of immune cells to sites of inflammation and injury. In recent years, it has become clear that the function of chemokines extends well beyond the role in leukocyte chemotaxis. They participate in organ development, angiogenesis/angiostasis, leukocyte trafficking and homing, tumorigenesis and metastasis, as well as in immune responses to microbial infection. Therefore, chemokines and their receptors are important targets for modulation of host responses in pathophysiological conditions and for therapeutic intervention of human diseases.     

Cellular polarization induced by chemokines: a mechanism for leukocyte recruitment?

Chemokines are known to induce leukocyte adhesion to the endothelium and emigration into tissues. Here, Miguel Angel del Pozo and colleagues discuss how these molecules also appear to regulate the redistribution of cell adhesion receptors. Recruitment of adhesion molecules towards a cellular uropod in response to chemokines may represent a novel cooperative mechanism in the recruitment of leukocytes to sites of inflammation.     

Chemokine decoy receptors: new players in reproductive immunology

Chemokines are multifunctional molecules with roles in leukocyte trafficking and developmental processes. Both fetal and maternal components of the placenta produce chemokines, which control leukocyte trafficking observed in the placenta. Thus, chemokines play roles in the balance between protection of the developing embryo/fetus and tolerance of its hemiallogeneic tissues. Recently, a group of chemokine receptors, which include D6, DARC, and CCX-CKR, have been described as "silent" receptors by virtue of their inability to activate signal transduction events leading to cell chemoattraction. Here we review in vitro and in vivo evidence indicating that chemokine "silent" receptors regulate innate and adaptive immunity behaving as decoy receptors that support internalization and degradation of chemotactic factors, and discuss available information on their potential role in reproductive immunology.     

Pathophysiological roles of chemokines in human reproduction: an overview

Chemokines are a group of small cytokines that have an ability to induce leukocyte migration. Chemokines exert their functions by binding and activating specific G protein-coupled receptors. Studies have unveiled pleiotropic bioactivities of chemokines in various phenomena ranging from immunomodulation, embryogenesis, and homeostasis to pathogenesis. In the mammalian reproductive system, chemokines unexceptionally serve in multimodal events that are closely associated with establishment, maintenance, and deterioration of fecundity. The aim of this review is to update the knowledge on chemokines in male and female genital organs, with a focus on their potential pathophysiological roles in human reproduction.     

T cells and their partners: The chemokine dating agency

Chemokines and their receptors have long been recognized as key molecules directing leukocyte migration between blood, lymph and tissues. Evidence accumulated in recent years indicates that, in addition to their chemotactic functions, chemokine receptors are highly versatile players fine-tuning immune responses. Chemokine receptors and ligands have been implicated in dendritic-cell maturation, signal transmission at the immunological synapse between T lymphocytes and their cellular partners, and in the polarization of immune responses. These findings identify new roles for chemokines in T-cell triggering and activation of effector functions, and suggest that these small cytokines represent key conductors of adaptive immunity.     

Chemokine Decoy Receptors: New Players in Reproductive Immunology

Chemokines are multifunctional molecules with roles in leukocyte trafficking and developmental processes. Both fetal and maternal components of the placenta produce chemokines, which control leukocyte trafficking observed in the placenta. Thus, chemokines play roles in the balance between protection of the developing embryo/fetus and tolerance of its hemiallogeneic tissues. Recently, a group of chemokine receptors, which include D6, DARC, and CCX-CKR, have been described as “silent” receptors by virtue of their inability to activate signal transduction events leading to cell chemoattraction. Here we review in vitro and in vivo evidence indicating that chemokine “silent” receptors regulate innate and adaptive immunity behaving as decoy receptors that support internalization and degradation of chemotactic factors, and discuss available information on their potential role in reproductive immunology.     

Chemokine regulation of normal and pathologic immune responses

Chemokines are small basic proteins that are the major mediators of all leukocyte migration. There are at least 46 distinct chemokines, and 19 chemokine receptors, making it easily the largest cytokine family. Chemokines can be both beneficial and harmful, by either stimulating an appropriate immune response to microbial invasion, or by mediating pathologic tissue destruction in many types of human disease. Chemokines have been implicated in the tissue destruction seen in autoimmune diseases, atherosclerosis, allograft rejection, and neoplasia. Chemokines also play essential roles in normal lymphocyte trafficking to primary and secondary lymphoid organs for antigen presentation and lymphocyte maturation. Chemokines also regulate hematopoietic stem and progenitor cell homing and proliferation. Therefore, it is likely that chemokines will become important targets for pharmacologic intervention in a wide variety of human diseases in the future.     

Immune cell migration in inflammation: present and future therapeutic targets

The burgeoning field of leukocyte trafficking has created new and exciting opportunities in the clinic. Trafficking signals are being defined that finely control the movement of distinct subsets of immune cells into and out of specific tissues. Because the accumulation of leukocytes in tissues contributes to a wide variety of diseases, these 'molecular codes' have provided new targets for inhibiting tissue-specific inflammation, which have been confirmed in the clinic. However, immune cell migration is also critically important for the delivery of protective immune responses to tissues. Thus, the challenge for the future will be to identify the trafficking molecules that will most specifically inhibit the key subsets of cells that drive disease processes without affecting the migration and function of leukocytes required for protective immunity.     

Chemokines

Motility is a hallmark of leukocytes, and breakdown in the control of migration contributes to many inflammatory diseases. Chemotactic migration of leukocytes largely depends on adhesive interaction with the substratum and recognition of a chemoattractant gradient. Chemokines are secreted proteins and have emerged as key controllers of integrin function and cell locomotion. Numerous distinct chemokines exist that target all types of leukocytes, including hematopoietic precursors, leukocytes of the innate immune system, as well as naive memory, and effector lymphocytes. The combinatorial diversity in responsiveness to chemokines ensures the proper tissue distribution of distinct leukocyte subsets under normal and pathological conditions. Inflammatory chemokines are readily detected in lesional tissue and local cellular infiltrates carry corresponding chemokine receptors. Blocking of inflammatory chemokines represents a promising strategy for the development of novel anti-inflammatory therapeutics.This review focuses on a separate class of chemokines, termed homeostatic chemokines, with steady-state production at diverse sites, including primary and secondary lymphoid tissues as well as peripheral (extralymphoid) tissues. More precisely, we discuss the chemokines involved in T-cell traffic during the initiation of adaptive immunity and compare the distinct migration properties of short-lived effector T cells and long-lived memory T cells. Memory T cells are currently classified according to the presence of the lymph node-homing receptor CCR7 into CCR7+ central memory T (T(CM)) cells and CCR7- effector memory T (T(EM)) cells. For better understanding memory T-cell function, we propose the distinction of a third category, termed peripheral immune surveillance T (T(PS)) cells, which typically reside in healthy peripheral tissues, such as skin, lung, and gastrointestinal tract.Localization and relocation of memory T cells is strictly related to their function in recall responses. Therefore, detailed knowledge of their generation and tissue distribution may help to design better vaccination strategies.     

A burgeoning family of biological mediators: chemokines and chemokine receptors

Chemokines are a superfamily of pro-inflammatory polypeptide cytokines that selectively attract and activate different cell types. Most of its members are small proteins that exhibit conserved cysteines in specific positions. Chemokines activate cells through their binding to shared or unique cell surface receptors which belong to the seven-transmembrane (STM), G-protein-coupled receptors (GPCRs). The large number of chemokines and chemokine receptors are indicative of the importance of these molecules in a variety of pathophysiological conditions.     

Chemokines and their receptors in allergic disease

Mechanisms of chemoattraction underlie the spatial organization of the cells of the immune system under basal conditions and the localization of these cells to sites of inflammation. The chemokines, a family of around 50 small proteins, play a major role in these processes. Leukocytes are equipped with cell-surface sensors for chemokines. There are 19 such receptors that are differentially expressed on leukocytes: the repertoire of receptor expression depending on the type of leukocyte and its stage in maturation. From observations in animal models, clinical studies, in vitro cell biology, and molecular analysis, a working hypothesis has been established to explain the cellular interactions underlying allergic responses and the chemokines-chemokine receptors involved. Chemokines signal through G protein-coupled receptors that are used typically for sensory functions (eg, detection of olfactory signals in the nose). This type of receptor can be blocked selectively by small-molecule antagonists. This provides the opportunity for the development of therapeutic compounds designed to suppress the recruitment of particular leukocyte types in allergic reactions.