Chemokines and brain functions

Chemokines are small secreted proteins that chemoattract and activate immune and non-immune cells both in vivo and in vitro. Besides their well-established role in the immune system, several recent reports have suggested that chemokines and their receptors may also play a role in the central nervous system (CNS). The best-known central action is their ability to act as immuno-inflammatory mediators. Indeed, these proteins regulate the leukocyte infiltration in the brain during inflammatory and infectious diseases. However, recent studies clearly demonstrate that chemokines and their receptors are constitutively expressed by glial and neuronal cells in the CNS, where they are involved in intercellular communication. The goal of this review is to summarize recent information concerning the role of chemokines in brain functions. The first part will focus on the expression of chemokines and their receptors in the CNS with the main spotlight on the neuronal expression. In the second part, we will discuss the role of chemokines and their receptors in normal brain physiology. Because several chemokines are involved in neuroinflammatory and neurodegenerative disorders, the role of chemokines and their receptors in these diseases is reviewed further in this section. In conclusion, the implication of chemokines in cellular communication could allow: i) to identify a new pathway for neuron-neuron and/or glia-glia and/or neuron-glia communications that are relevant to both normal brain function and neuroinflammatory and neurodegenerative diseases; ii) to develop new therapeutic approaches for still untreatable diseases further.     

Chemokines and their receptors in central nervous system disease

Almost a decade ago, it was discovered that the human deficiency virus (HIV) makes use of chemokine receptors to infect blood cells. This appreciation of the clinical relevance of specific chemokine receptors has initiated a considerable boost in the field of chemokine research. It is clear today that chemokine signaling orchestrates the immune system and is widely involved in both physiological and pathophysiological processes. Since the chemokine system offers various targets through which pathology could be influenced, most pharmaceutical companies have chosen this system as a therapeutic target for a variety of diseases. Here recent developments concerning the role of chemokines in diseases of the central nervous system (CNS) as well as their possible therapeutic relevance are discussed.     

Chemokine blockers--therapeutics in the making?

Chemokines are a family of small chemoattractant cytokines that have an important role in controlling leukocyte migration. The finding that some chemokines and their receptors are upregulated in both acute and chronic inflammatory diseases, and that they are key players in the development of AIDS, has provided the pharmaceutical industry with new targets for therapeutic intervention in these diseases. Although the chemokine system shows apparent redundancy in vitro, target validation is possible largely through expression studies in human disease tissues and the use of transgenic and knockout mice as disease models. Several approaches are being developed to block the effects of chemokines, including small-molecule antagonists of chemokine receptors, modified chemokines and antibodies directed against chemokine receptors. Here, we describe the rationale behind these different approaches, the pitfalls that have been encountered and future perspectives.     

Inflammation and autoimmunity as a central theme in neurodegenerative disorders: fact or fiction?

Irrespective of the initiating stimuli, neurodegenerative disorders including multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease and stroke share many characteristics of inflammation and autoimmunity. This review summarizes and correlates the information relating to the role of cytokines and chemokines in initiating and propagating the inflammatory/immune response in these pathologies. For example, in MS there is a continuous realignment in the inflammatory and immune response. However, due to the redundancy in the cytokine/chemokine response, it is extremely unlikely that any one therapy will be successful in treating neurodegenerative diseases. This review attempts to highlight specific targets for therapeutic intervention.     

Chemokines in renal diseases

The interaction of activated leukocytes and renal resident cells is thought to play a crucial role in the pathogenesis of renal diseases. Recent investigations of the pathophysiological roles of chemokines and their cognate receptors have shed light on the detailed molecular mechanisms of leukocyte trafficking and activation in the diseased kidneys. Chemokine/chemokine receptor systems may be essentially involved in the pathogenesis of phase-specific renal disorders and the measurement of urinary levels of chemokines may be clinically useful for monitoring the different disease phases and activities. In addition, chemokine receptors expressed in renal resident cells may be involved in proliferation, fibrogenesis, as well as chemotaxis. The selective intervention of chemokine/chemokine receptor systems (anti-chemokine therapy) may have the potential as the particular therapeutic strategies for renal diseases in future.     

The role of chemokines in recruitment of immune cells to the artery wall and adipose tissue

The role of the immune system is to recognize pathogens, tumor cells or dead cells and to react with a very specific and localized response. By taking advantage of a highly sophisticated system of chemokines and chemokine receptors, leukocytes such as neutrophils, macrophages, and T-lymphocytes are targeted to the precise location of inflammation. While this is a beneficial process for acute infection and inflammation, recruitment of immune cells to sites of chronic inflammation can be detrimental. It is becoming clear that these inflammatory cells play a significant role in the initiation and progression of metabolic disorders such as atherosclerosis and insulin resistance by infiltrating the artery wall and adipose tissue (AT), respectively. Data from human studies indicate that elevated plasma levels of chemokines are correlated with these metabolic diseases. Recruitment of macrophages to the artery wall is well known to be one of the first steps in early atherosclerotic lesion formation. Likewise, recruitment of macrophages to AT is thought to contribute to insulin resistance associated with obesity. Based on this knowledge, much recent work in these areas has focused on the role of chemokines in attracting immune cells (monocytes/macrophages in particular) to these 2 sites. Thus, understanding the potential for chemokines to contribute to metabolic disease can help direct studies of chemokines as therapeutic targets. In this article, we will review current literature regarding the role of chemokines in atherosclerosis and obesity-related insulin resistance. We will focus on novel work showing that chemokine secretion from endothelial cells, platelets, and adipocytes can contribute to immune cell recruitment, with a diagram showing the time course of chemokine expression and leukocyte recruitment to AT. We will also highlight a few of the less-commonly known chemokine–chemokine receptor pairs. Finally, we will discuss the potential for chemokines as therapeutic targets for treatment of atherosclerosis and insulin resistance.     

Chemokines as mediators for intercellular communication in the brain

Chemokines constitute a large and still growing family of structurally-related small (8-10 kDa) cytokines that have chemotactic activity for leukocytes. Recently, some receptors for chemokines were reported to be used as a co-receptor by HIV at infection. In addition to their well-established role in inflammatory response and recently-reported role as a co-receptor for HIV, recent data suggest that chemokines and their receptors physiologically and pathologically play crucial roles as the mediators for intercellular communication among the cells intrinsic to and recruited into the brain; i.e., neurons, astrocytes, microglia, endothelial cells and leukocytes. Some chemokines such as SDF-1 and fractalkine are constitutively produced in the brain, implicating that they have an important role in maintenance of CNS homeostasis or determination of the patterning of neurons and/or glial cells in developing brain and normal adult brain. Chemokines such as MCP-1, MIP-1 alpha and CINC were shown to be induced by various neuroinflammatory stimuli, suggesting that they are involved in various neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, stroke and AIDS dementia syndrome. Chemokines and their receptors are potential targets for therapeutic intervention in neurodegenerative diseases.     

Targeting chemokines in proteinuria-induced renal disease

INTRODUCTION: Proteinuria is a common finding in glomerular diseases that contributes to the progression of chronic kidney injury. Tubular cells reabsorb the excess of albumin and other plasma proteins from the tubular lumen, triggering several pathophysiologic responses, such as overexpression of fibrogenic mediators and inflammatory chemokines. Chemokines are implicated both in the recruitment of inflammatory infiltrate and in a number of physiological and pathological processes related to protein overload. AREAS COVERED: In recent years, the specific chemokines and their receptors and the intracellular signaling pathways involved in proteinuria-induced renal damage have been identified. This review provides an overview of the role of chemokines and their receptors in proteinuria-related renal disease and summarizes novel therapeutic approaches to restrain the progression of renal damage. EXPERT OPINION: Inhibition of chemokine-induced biological activities is a promising therapeutic strategy in proteinuric disorders. Neutralizing antibodies and small organic molecules targeting chemokines and chemokine receptors have been proven to prevent inflammation and renal damage in experimental models of protein overload. Some of these compounds are currently being tested in human clinical trials.     

Targeting the chemokine system for multiple sclerosis treatment

Multiple sclerosis (MS) is the most common demyelinating disorder of the human central nervous system (CNS). The typical pathological hallmark of active MS is the presence of inflammatory foci disseminated in the CNS. It is believed that the composition of inflammatory infiltrates is determined in part by the spectrum of chemokines produced in a focus of inflammation. Numerous studies suggest chemokine involvement in MS pathogenesis. Interfering with chemokine-chemokine-receptor interactions may potentially lead to prevention and/or amelioration of CNS inflammatory processes. Initial studies to obtain 'proof-of-principle' used neutralizing antibodies in small animal models of MS. The subsequent generation of chemokine receptor inhibitors were modified chemokine peptides. At present, the development of small molecule antagonists to chemokine receptors is the dominant approach. Current evidence suggests that chemokines and their receptors are promising targets for effective treatment of MS and other CNS inflammatory and autoimmune diseases.     

Opportunities for novel therapeutic agents acting at chemokine receptors

Chemokines are proinflammatory mediators that primarily control leukocyte migration into selected tissues and upregulation of adhesion receptors. They also have a role in pathological conditions that require neovascularization and are implicated in the suppression of viral replication. By interaction with their respective G-protein-coupled receptor, chemokines have a profound influence over the selective recruitment of specific cell types in acute inflammatory disease and, hence, inhibition of their action should be of therapeutic benefit. Only now are small molecule inhibitors becoming available to validate this speculation. In this review, without seeking to be comprehensive, the authors provide an introduction to chemokines, their receptors and their role in certain disease processes. Also, recent disclosures claiming novel nonpeptide ligands for chemokine receptors are summarized.     

Chemokines as novel therapeutic targets in inflammatory diseases

Chemokines and their receptors are a large family of inflammatory molecules responsible for a number of biological functions, including the accumulation of leukocytes at tissue sites. Over the past 10 years, a number of studies have indicated a role for chemokines and chemokine receptors in the pathophysiology of several inflammatory diseases, examples of which are multiple sclerosis, atherosclerosis, rheumatoid arthritis, and gastrointestinal diseases including hepatic disease. For this reason, it is not surprising that modulation of their pharmacology could be a prime target for drug discovery. This commentary provides a brief synopsis of our current knowledge of the role of chemokines and their receptors in the inflammatory process, and highlights the pros and possibly cons of chemokine and chemokine receptor antagonism in the therapeutic approach to several inflammatory diseases.     

The expression and function of chemokines involved in CNS inflammation

Chemokines and their receptors have principal roles in leukocyte trafficking under normal physiological and pathological conditions. The differential expression of the chemokine system in different parts of the CNS provides insights into the processes that are required for normal immune surveillance and pathological immune-mediated effector processes. Insights derived from studying multiple sclerosis, an inflammatory disorder of the CNS in humans, and experimental autoimmune encephalomyelitis, an animal model of this disorder, aid in further understanding the complexities of chemokine-mediated inflammation. Knowledge of the molecular biology of chemokines and their receptors, and the roles of specific chemokine ligands and receptors in the CNS in health and in disease have made these proteins targets for therapeutic intervention in neuroinflammation. We also discuss currently proposed and potentially useful chemokine receptor antagonists.     

Antiapoptotic drugs: a therapautic strategy for the prevention of neurodegenerative diseases

The purpose of this review is to discuss potential pathways involved in the pathogenesis of neurodegenerative diseases, highlighting current pharmacological drug targets in neuronal apoptosis prevention. The incidence of these disorders is expected to rise in the coming years and so finding effective treatments represents a significant challenge for medicine. Alzheimer's disease and Parkinson's disease were both described almost a century ago and are the most important neurodegenerative disorders in the developed world. However, the molecular mechanisms that lead to the development of the neuronal pathology in both diseases are unclear. For this reason, despite substantial research in the area, an effective treatment for these diseases does not yet exist. In the present study we discuss in depth the pathways involved in apoptosis and neuronal death in neurodegenerative diseases. We also examine drugs that may have a neuroprotective effect. Inhibition of apoptosis mediated by oxidative stress generation and mitochondrial alteration or by the blockade of NMDA receptors could constitute a suitable therapeutic strategy for Alzheimer's disease. A multiple therapy with antioxidants, cell cycle inhibitors, GSK3β inhibitors, and STATINS could, in the future, represent a suitable strategy for delaying the progression of neurodegenerative diseases. This research contributes to the development of new methods in the field of apoptosis inhibitors that could provide the future tools for the treatment of Alzheimer's and Parkinson's disease, as well as other neurodegenerative diseases.     

Targeting chemokines in proteinuria-induced renal disease

Introduction: Proteinuria is a common finding in glomerular diseases that contributes to the progression of chronic kidney injury. Tubular cells reabsorb the excess of albumin and other plasma proteins from the tubular lumen, triggering several pathophysiologic responses, such as overexpression of fibrogenic mediators and inflammatory chemokines. Chemokines are implicated both in the recruitment of inflammatory infiltrate and in a number of physiological and pathological processes related to protein overload.

Areas covered: In recent years, the specific chemokines and their receptors and the intracellular signaling pathways involved in proteinuria-induced renal damage have been identified. This review provides an overview of the role of chemokines and their receptors in proteinuria-related renal disease and summarizes novel therapeutic approaches to restrain the progression of renal damage.

Expert opinion: Inhibition of chemokine-induced biological activities is a promising therapeutic strategy in proteinuric disorders. Neutralizing antibodies and small organic molecules targeting chemokines and chemokine receptors have been proven to prevent inflammation and renal damage in experimental models of protein overload. Some of these compounds are currently being tested in human clinical trials.     

Toll-like receptors are key players in neurodegeneration

The activation of innate immune response is initiated by engagement of pattern-recognition receptors (PPRs), such as Toll-like receptors (TLRs). These receptors are expressed in peripheral leukocytes and in many cell types in the central nervous system (CNS). The expression of TLRs in CNS was mainly studied in astrocytes and microglial cells. However, new evidence indicates that these receptors may play an important role in neuronal homeostasis. The expression of TLRs in the CNS is variable and can be modulated by multiple factors, including pro-inflammatory molecules, which are elevated in neurodegenerative diseases and can increase the expression of TLRs in CNS cells. Moreover, activation of TLRs induces the release of pro-inflammatory cytokines. Therefore, TLRs have been shown to play a role in several aspects of neurodegenerative diseases. Here we will discuss results reported in the recent literature concerning the participation of TLRs in neurodegenerative diseases.     

Nicotinic systems in central nervous systems disease: degenerative disorders and beyond

Advances in the understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors has provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realization that such receptors are changed in degenerative neurologic diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Ongoing investigations of the molecular substructure of CNS nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioral, motor, and sensory functioning. Clues from careful studies of human cognition and behavior are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Modulation of these receptors with the ultimate goal of producing therapeutic benefits is the goal of these investigations and drug development. This paper will review studies from our laboratory and others that point to the importance of CNS nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in disease states. In addition, this paper will examine potential clinical applications of nicotine and/or nicotinic agonists in a variety of CNS disorders with particular emphasis on structural brain disease including: movement disorders such as Parkinson's disease and Tourette's syndrome, cognitive/behavioral disorders such as Alzheimer's disease, attention deficit/hyperactivity disorder, and schizophrenia, and other more speculative applications. Important results from early therapeutic studies of nicotine and/or nicotinic agonists in these disease states are presented. For example, recent studies with nicotine and novel nicotinic agonists such as ABT-418 by our group in AD patients suggest that nicotinic stimulation can improve the acquisition and retention of verbal information and decrease errors. Preliminary results from a series of studies examining the acute and subchronic quantitative effects of nicotine on cognitive and motor functioning in Parkinson's disease suggest that acute nicotine administration and stimulation improves some aspects of cognitive and motor performance and may improve the processing speed of more complex tasks. The most likely near-term applications of novel nicotinic agonists in CNS disorders are likely to be in those disorders that are degenerative in nature, e.g. Parkinson's disease and Alzheimer's disease, or other movement disorders such as Tourette's syndrome. The most likely direct therapeutic role for nicotinic agonists is as augmentation therapy in combination with other agents rather than as monotherapy, except early in disease states or as a prophylactic or preventative treatment.     

Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases

Chemokines are members of the chemoattractant cytokine family. They play key roles in the trafficking of leukocytes and in the induction of chemotaxis through the activation of G protein-coupled receptor. Considerable interest has been paid to these molecules to elucidate their roles in the unique inflammatory responses elicited in the central nervous system (CNS). Chemokine CCL2 (also known as monocyte chemoattractant protein-1, MCP-1) is one of the vital chemokines that control the migration and infiltration of monocytes/macrophages. CCL2 and its receptor CCR2 have been shown to be induced and involved in various neurodegenerative disorders including Alzheimer’s disease, multiple sclerosis, and ischemic brain injury. The present review will focus on the biological and pathophysiological aspects of CCL2 and CCR2 in the CNS and the possible therapeutic approaches for targeting these two proteins to combat neurodegenerative diseases.     

Chemokines and antagonists in non-Hodgkin's lymphoma

Background: Chemokines and their receptors are a large family of molecules that control the trafficking of immune cells during their development and in response to inflammation. Non Hodgkin's lymphoma (NHL) derives from the neoplastic transformation of lymphocytes at different stages of differentiation and may show systemic, nodal and extranodal localisation as well as metastasis in different sites. Objective: To investigate the role of the chemokine system in the pathology of NHL and as a potential drug target in this disease. Method: The expression of chemokines and receptors by different NHL subtypes as well as their likely functional role in terms of lymphoma tissue localisation, lymphoma growth, tumour angiogenesis and recruitment of immune cells are reviewed. The data regarding antagonists or chemokines as potential therapeutic agents for NHL is discussed. Results/conclusions: NHL's express functional chemokine receptors, which, at least in part, dictate tissue localisation and perhaps metastatic potential. Different types of chemokine antagonists have been tested in vitro and in vivo and several peptide or small molecule inhibitors have reached Phase I/II clinical trials for different diseases. Although the field is in its early days, interesting compounds are being developed, directed especially against homeostatic chemokine receptors.     

Repulsive Guidance Molecule-a and Demyelination: Implications for Multiple Sclerosis

Drug development for neurodegenerative and neuroinflammatory diseases such as multiple sclerosis and traumatic brain injury is challenging. One promising strategy is to target a molecule with multiple biological actions affecting divergent pathophysiological disease phases simultaneously since these diseases arise from multiple pathological phases. In recent years, we pursued this strategy with a focus on multiple sclerosis and spinal cord injury and found that repulsive guidance molecule-a (RGMa) inhibits regeneration of injured CNS axons following spinal cord injury. We also found that RGMa enhances CD4(+) T cell activation facilitating CNS demyelination in an animal model of MS, mouse experimental autoimmune encephalomyelitis (EAE), which supports the idea that RGMa has distinct pathological actions. The multiple functions of RGMa in the CNS and the immune system would provide a therapeutic opportunity to concurrently block the autoimmune reactions and axon injury in neurodegenerative and neuroinflammatory diseases. In this article, we introduce the therapeutic potential of targeting RGMa as a novel intervention for MS and spinal cord injury.     

Endothelial chemokines in autoimmune disease

Compelling evidence now exists supporting the involvement of chemokines in the pathogenesis of autoimmune diseases. Examples of chemokines and chemokine receptors being involved in mediating autoimmune disease exist for rheumatoid arthritis, multiple sclerosis, allograft rejection, systemic lupus erythematosus, psoriasis, atopic dermatitis, lichen planus, and graft-versus-host-disease. Expression of chemokines by endothelial cells appears to be an important step in the development of these diseases. Since chemokines are small molecular weight molecules that act through G-protein coupled receptors, they make attractive drug targets. Several antagonists of chemokine - chemokine receptor interactions have been used to successfully alleviate some or all of the symptoms associated with many of these diseases in animal models. Further investigation of the involvement of chemokines in the pathogenesis or progression of autoimmune diseases may lead to practical clinical advances in diagnosis, prognosis, and therapy of such diseases.