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.     

Chemokines and their receptors in allograft rejection

Despite current recognition of over 40 chemokines and more than 18 chemokine receptors, understanding of their role in transplant immunobiology and transplant rejection is extremely limited and fragmentary. Recent literature has demonstrated the presence of chemokines and their receptors in transplants and some studies demonstrate important functional roles.     

Chemokine receptors and their antagonists in allergic lung disease

The trafficking and homing of leukocytes in normal homeostasis and in disease is under the control of a variety of cytokine and lipid mediators. One family of small cytokines particularly involved in inflammation which has been identified is the chemokine family. Their action is mediated by a large superfamily of seven transmembrane spanning G-protein coupled receptors. One of the hopes in this field has been there may be selectivity in terms of which cells are recruited to sites of inflammation by virtue of their chemokine receptor expression pattern. This means that it may be possible to find antagonists of chemokine receptors that can selectively down regulate certain cell type recruitment, without provoking a generalized immunosuppression. In this review, we discuss the current state of understanding of the chemokine receptor field. The therapeutic potential of this field can be judged from recent data on the use of protein chemokine antagonists in allergic disease. The data so far obtained in animal studies point to the potential clinical uses of this emerging class of therapeutic agents.     

Chemokines and chemokine receptors in scleroderma

Scleroderma is a connective tissue disease with unknown etiology characterized by excessive deposition of extracellular matrix in the skin. Cellular infiltrates of certain immune cells and proinflammatory mediators are suggested to play a crucial role in cutaneous fibrosis, forming complicated networks between fibroblasts and immune cells via cell-cell communications. Tissue-selective trafficking of leukocytes is mediated by combinations of adhesion molecules and chemokines. Recent studies have shown that an increase in proinflammatory chemokines has been associated with the initiation and/or development of skin fibrosis/sclerosis, suggesting that chemokines and their receptors may be important mediators of inflammation and fibrosis in scleroderma. This review will focus on the roles of chemokines and their receptors during the process of cutaneous sclerosis and will also provide a current insight into the potential mechanisms of scleroderma.     

Chemokines and their receptors in whiplash injury: elevated RANTES and CCR-5

The human sufferings and socioeconomic burden due to whiplash-associated disorders (WAD) are obvious but the pathogenesis of WAD is obscure. The possible involvement of the immune system during the disease process in WAD is not known. Effector molecules including chemokines and their receptors could play a role in WAD. In a prospective study using flow cytometry, we examined percentages of blood mononuclear cells (MNC) expressing the chemokines RANTES, MCP-1, MIP-1, MIP-1, and IL-8, the chemokine receptor CCR-5, the T cell activation marker CD25, and the T cell chemoattractant IL-16 in patients with WAD and, for reference, in healthy controls. Higher percentages of RANTES-expressing blood MNC and T cells were observed in patients with WAD examined within 3 days compared to 14 days after the whiplash injury and, likewise, compared with healthy controls. The patients with WAD examined within 3 days after the accident also had higher percentages of CCR-5-expressing blood MNC, T cells, and CD45RO+ T cells compared to healthy controls. In contrast, there were no differences for any of these variables between patients with WAD examined 14 days after injury and healthy controls. In conclusion, WAD is associated with a systemic but transient dysregulation in percentages of RANTES and CCR-5 expressing MNC and T cells.     

Chemokines and disease

We examine here several diseases that are associated with inappropriate activation of the chemokine network. Detailed comment has been restricted to pathological states for which there are compelling data either from clinical observations or animal models. These include cardiovascular disease, allergic inflammatory disease, transplantation, neuroinflammation, cancer and HIV-associated disease. Discussion focuses on therapeutic directions in which the rapidly evolving chemokine field appears to be headed.     

Toll-like receptors and immune response in allergic disease

Allergic reactions are dominated by the preferential development of specific Th2 responses against innocuous antigens in atopic individuals. This can reflect alterations in innate immune mechanisms. Toll-like receptors (TLRs) have evolved as key molecules., in innate and adaptive immunity. Their activation by structurally distinct exogenous or endogenous, ligands present at the cell microenvironment plays a critical role in antimicrobial defense. The global view is that TLR activation induces antigen-presenting, cells to produce cytokines that favor Th1-type immune responses, suggesting that it might prevent the development of deleterious Th2 responses in allergy. On the basis of epidemiological studies and recent data, it has been established that TLRs play a role in the development of Th2 responses. However, more information is needed to fully understand the mechanism of TLR involvement and the implication of immune cells that express TLRs in the Th1/Th2 cytokine profiles. Several TLRs, such as TLR9, TLR7, and TLR8, can be considered as good target candidates. Some TLR ligands, such as CpG DNA, are effective adjuvants, strong inducers of both IL-5 and eosinophilia downregulation. They are also potential links to allergen epitopes that could provide new allergen-specific immunotherapy regimens for the treatment of allergic disorders.     

Immunobiology of toll-like receptors in allergic disease

Allergic diseases prevalence rates have increased dramatically over the last 50 years in developed countries and one explanation might be that modern practices in public health lead to a decreased exposure towards pathogens resulting in a misguided immune response. Recently, it has become evident that immune responses against pathogens are initiated by Toll-like receptors (TLRs) that recognize a variety of structures derived from viruses, bacteria, fungi or protozoa. In this review we will discuss TLR ligands, TLR signaling in regard to Th1 and Th2 immune responses, their involvement in the development and their therapeutic potential in treatment of allergic disease.     

Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression

Although almost every known chemokine and chemokine receptor is expressed at some stage during development of allograft rejection, mechanistic studies indicate that the actual key effector mechanisms are rather few. Thus, in vivo studies have alleviated concerns regarding possible biological redundancy and the pleiotropic effects of these molecules, and have resulted in a focus on CXCR3, CCR5 and their respective ligands as key mediators of host alloresponses, especially in acute rejection. Data are also accruing regarding the importance of chemokine/chemokine receptor pathways in ischemia/reperfusion, chronic rejection and tolerance induction following co-stimulation blockade, providing new targets for immune monitoring and therapeutic intervention.     

Chemokines and chemokine receptors in rheumatoid arthritis

Chemokines are chemotactic cytokines involved in a number of pathological processes, including inflammatory conditions. Chemokines play a role in the pathogenesis of various inflammatory diseases. Based on a burgeoning body of literature, RA was chosen as a prototype to discuss this issue. In this review, the authors give a detailed introduction to the classification and function of chemokines and their receptors. This is followed by a discussion of the role of chemokines and chemokine receptors in RA. Chemokines interact with other inflammatory mediators, such as cytokines. Thus, the regulation of chemokine production and the place of chemokines in the network of inflammatory mediators present in the rheumatoid synovium are also reviewed. Finally, potential strategies using anti-chemokine or anti-chemokine receptor biologicals in anti-rheumatic therapy are discussed.     

Chemokines, chemokine receptors and pain

Many patients suffer from neuropathic pain as a result of injury to the peripheral nervous system (e.g. post-herpetic neuralgia or diabetic neuropathy) or to the central nervous system (e.g. spinal cord injury or stroke). The most distinctive symptom of neuropathic pain is allodynia, whereby normally non-painful stimuli, such as light touch, become painful. Traditionally, inflammatory and neuropathic pain syndromes have been considered distinct entities; however, recent evidence belies this strict dichotomy. Nerve damage can stimulate macrophage infiltration and increase the number of activated T cells. Under these conditions, neuroinflammatory and immune responses contribute as much to the development and maintenance of pain as the initial damage itself. Recently, studies using animal models have shown that upregulation of chemokines is one of the mechanisms underlying the development and maintenance of chronic pain.     

Chemokines, chemokine receptors and allergy

Chemokines are a group of cytokines that are responsible for the influx of blood cells, including T and B lymphocytes, monocytes, neutrophils, eosinophils and basophils, in allergic and other inflammatory conditions. They function as G protein-coupled chemotactic factors which also activate the cells with which they interact. Certain chemokines function within the afferent arm of the immune system, in which antigen is processed and antibody formation initiated, and others are active within the effector pathways of cellular immunity and late-phase allergic reactions. Th2 lymphocytes, which are critical for allergy, employ the CC chemokine receptors CCR4 and CCR8 with the ligands thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and I-309, respectively. The chemokine receptor CCR3 and ligands monocyte chemoattractant protein (MCP)-3, MCP-4, regulated upon activation normal T cell expressed and secreted (RANTES) and eotaxins I and II are of particular relevance for the recruitment and activation of eosinophils. Th1 reactions depend upon interferon gamma-induced CXC chemokines interferon- inducible protein (IP)-10, interferon-inducible T cell-alpha chemoattractant (iTAC) and monokine induced by interferon-gamma (MiG), which bind to chemokine receptor CXCR3.     

Chemokines in autoimmune disease

Growing evidence indicates that structural cells play a crucial role in the chronic inflammation of autoimmunity by their recruitment of chemokine-dependent cells. Members of the two functional classes of chemokines, inflammatory and homeostatic, seem to be involved in lymphocyte recruitment and survival, and in establishing ectopic lymphoid structures in the target organs of autoimmune diseases. Results from animal models suggest that chemokines are reasonable therapeutic targets in autoimmunity.     

Chemokines and chemokine receptors in inflammation of the CNS

Chemokines are small chemotactic cytokines involved in numerous biologic and pathologic processes. They are important mediators of leukocyte trafficking, development of inflammation, tumor metastasis and immune cell differentiation. Inflammation in the CNS develops in a unique manner that is partially due to the existence of the blood–brain barrier. All inflammatory cells migrate to the CNS through the blood–brain barrier in a multistep process of cell–cell interactions. The key players involved in this transmigration are adhesion molecules and chemokines. Substantial knowledge about involvement of chemokines and their receptors in the immune-mediated CNS inflammation has been accumulated in recent years. Initially, these studies involved animal models of neuroinflammation, however, later studies on human diseases were performed. Results obtained in these experiments confirmed the significant role of the chemokine system in certain pathologies. These observations suggest that antichemokine strategies may be beneficial in the treatment of immune-mediated CNS inflammation.