Regulation Of Chemokine Receptor Interactions And Functions

This book is a printed edition of the Special Issue "Regulation of Chemokine-Receptor Interactions and Functions" that was published in IJMS

A hallmark of inflammation is the accumulation of leukocytes, which can serve to remove pathogens and necrotic tissue, but may also damage healthy tissue and exacerbate the inflammatory response. Our understanding of leukocyte recruitment in inflammation was revolutionized in the late 1980s by the discovery of chemokines (chemotactic cytokines), a family of small, secreted proteins that induce migration of selective subsets of leukocytes. Shortly afterwards, chemokines were found to exert their functions through the now familiar chemokine receptors, members of the G protein-coupled receptor superfamily. As their physiological and pathological functions were elucidated, chemokine receptors have become popular targets for drug development in inflammatory diseases as well as cancer metastasis and HIV infection. Extensive research has revealed that the functions of chemokines and their receptors are regulated at numerous levels, including: genetic mutations/polymorphisms; control of expression levels; ligand internalization via functional or decoy receptors; intrinsic selectivity of chemokine-receptor binding; hetero- or homo-oligomerization of chemokines or of receptors; alternative signalling pathways; interaction of chemokines with glycosaminoglycans; post-translational modifications; and binding to pathogen-derived inhibitors. This Special Issue of IJMS focused on the natural and pharmacological mechanisms by which the activities of chemokines and their receptors can be regulated.

Chemokine Receptors and NeuroAIDS: Beyond the Co-receptor Function and Links to Other Neuropathologies focuses on unresolved or emerging issues concerning the role of chemokine receptors in neuronal injury and HIV neuropathology, including their ability to regulate fundamental neuronal and glial functions and their role in neurovirulence and neurotoxicity. Although the importance of these molecules in the CNS physiology and pathology is now apparent, these issues are still matter of debate, and further research is required to design effective pharmacological agents that specifically target the brain chemokine system without major side effects. To this end, specific topics have been selected and are reviewed by international experts within the basic science/medical community. This book encourages investigation in the most controversial areas and fosters interaction between clinicians and basic scientists. The book also increases awareness about differences in disease progression among different parts of the world as well as selected patient populations, which may also help identifying novel therapeutic strategies.

Chemokines constitute a large family of structurally similar cytokines that contain a signature of conserved cysteine residues joined by disulfide bridges. Binding of chemokines to specific G protein-coupled receptors followed by downstream signaling defines their biological function. Initially, chemoattraction was the key function linked to chemokines/chemokine receptors; however, in recent years, it has become clear that chemokine ligand-receptor interactions can also modulate cellular activation, survival, and proliferation, among other functions in homeostatic and diseased states. Importantly, major advances in our understanding of chemokine biology have led to chemokine receptors becoming specific therapeutic targets with great potential. In Chemokines: Methods and Protocols, expert researchers provide practical information regarding experimental models and state of the art protocols used to delineate chemokine/chemokine receptor function and their applications in health and disease. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Practical and easy to use, Chemokines: Methods and Protocols aims to reveal key protocols of functional and descriptive chemokine ligand/receptor assays that will be of practical significance to graduate students, post-doctoral fellows, trainees, and researchers in academia and industry.

Chemokines are involved in cell migration and activation during routine immune surveillance, inflammation and even cancer metastasis. The migration of chemokine receptor-bearing cells, including leukocytes and tumor cells, occurs in response to the secretion of chemokines, which accumulate on cell surfaces through interaction with glycosaminoglycans (GAGs) where they effectively serve as traffic signals to guide cell movement. Engagement of chemokines with their receptors subsequently causes the activation of signaling pathways that result in firm adhesion and extravasation of the cell into tissue, and in the case of leukocytes, activation of defense mechanisms. However, in cancer cells, the signaling pathways can be exploited or redirected, resulting in responses like survival, growth and proliferation. Herein, a structural and functional approach was used to address specific questions about the interactions of chemokines (i) with GAGs and (ii) with chemokine receptors in the context of cancer. Technically, the use of mass spectrometry has been a strong theme throughout these studies. In Chapter 2, a novel application of hydroxyl radical footprinting coupled with mass spectrometry was used to characterize the GAG binding specificity of the chemokine, MCP-3/CCL7. Potential GAG binding epitopes, identified by mass spectrometry, were then validated by mutagenesis and functional assays. In Chapter 3 and 4, a phosphoproteomic mass spectrometry strategy was used to elucidate CXCL12-mediated survival signaling through the receptor, CXCR4, in cells from patients with chronic lymphocytic leukemia (CLL). While signaling cascades involved in chemokine-mediated migration are well established, pathways involved in cell survival and proliferation in cancer, are not. Methods developed for phosphopeptide enrichment, and subsequent analysis via mass spectrometry are described in Chapter 3, and interesting/novel phosphoproteins, potentially involved in CXCL12-mediated CLL survival are described in Chapter 4. In Chapter 5, a functional approach was taken to elucidate the roles of receptors CXCR4 and CXCR7 in breast cancer growth and metastasis. The data show that CXCR7 affects the functional activity of CXCR4 in vitro, and decreases the extent of lung metastases in vivo, without inhibiting primary tumor growth. Overall, these studies serve to better understand some of the regulatory mechanisms that control chemokine function in normal physiology and in cancer.

Chemokines are hormone-like signaling molecules secreted by cells to signal infection and guide the immune response. Following a decade of basic chemokine research, the pharmaceutical industry has now begun to exploit this crucial signaling pathway for the development of innovative drugs against AIDS, cancer, neural and autoimmune diseases. Here is the first reference focusing on these novel drug development opportunities. Opening with a general introduction on chemokine function and chemokine receptor biology, the second part covers the known implications of these signaling molecules in human diseases, such as cancer, neural disorders, and viral infection, including AIDS. The third part systematically surveys current drug development efforts at targeting individual chemokine receptors, as well as other chemokine interaction partners, including up-to-date reports from the pharmaceutical industry.

Chemokines play an important role in recruiting inflammatory cells into tissues in response to infection and inflammation. They also play an important role in coordinating the movement of T-cells, B-cells and dentritic cells, necessary to generate an immune response (response to injury, allergens, antigens, invading microorganisms). They selectively attract leukocytes to inflammatory foci, inducing both cell migration and activation. They are involved in various diseases, like atherosclerosis, lung and skin inflammation, multiple sclerosis, or HIV. Volume 1 of this two-volume set discusses the immunobiology of chemokines. It is divided into two parts: a) cellular targets in innate and adaptive immunity, and b) effector cell traffic-unrelated functions. Together with volume 2, which discusses the pathophysiology of chemokines, both volumes give a comprehensive overview of chemokine biology.

This volume in the Current Topics in Membranes series discusses the biology of chemokines and their binding partners, chemokine receptors, in normal and disease-related states. Chemokines are small proteins that are important in normal immune responses. Recent research demonstrates a role for these proteins in a variety of diseases such as heart disease, allergy, asthma, and cancer. As a result of the discovery of this link to disease, the topic of chemokines and drugs that block their actions has become an intense are of study. This book presents the topics of chemokines, chemokine receptors, and related pathologies in an integrated manner that provides the reader with a comprehensive and up-to-date knowledge of these topics. Provides a comprehensive overview of the history, molecular biology, cell biology, pharmacology, physiology, and pathophysiology of chemokines and their receptors Each chapter discusses "future directions and unanswered questions" of chemokine biology Serves as a road map for future research