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Chemokines were initially discovered in the context of inflammatory pathologies and were the curiosity of a limited number of researchers. Receptors for these cytokine molecules were identified shortly thereafter and determined to be members of the large G protein-coupled receptor (GPCR) superfamily. Collectively, these basic observations provided a framework to understand mechanisms by which leukocyte subsets could migrate into tissues in a specific manner. Nonetheless, as the field evolved, so came a realization of the broader impact of this family on diverse biological processes, which include the regulation of leukocyte trafficking in hematopoiesis, innate and adaptive immunity, angiogenesis, cancer, and viral pathogenesis. We begin this volume with an overview of research on chemokines and their receptors and then subsequently migrate into a brief discussion of key findings that defined the maturation of this field. As members of the GPCR superfamily have historically dominated drug development programs, so too has interest in chemokine receptors as therapeutic targets.

This chapter provides an overview of the literature in the field of the structural biology of chemokines. The secondary, tertiary, and quaternary structures as determined by x-ray crystallography and nuclear magnetic resonance are compared among the four chemokine families. The biological significance of chemokine structures is explored through a discussion of additional molecules that interact with the chemokines. Specific interactions of chemokines and their receptors are discussed as are interactions between chemokines and glycosaminoglycans. Additionally, a set of tables and figures summarizes the structural information available in the databases.

To date, all mammalian chemokine receptors and chemokine-binding proteins belong to the seven-transmembrane (7TM)-spanning family of receptors, which are typically, although not exclusively, coupled to G proteins . The large G protein-coupled receptor (GPCR) family comprises almost 1000 members in the human genome accounting for in excess of 3% of transcribed sequences. This family is subdivided into the class A, B, C, and F/S families on the basis of shared motifs, and chemokine receptors specifically belong to the class A GPCR family. This review summarizes the current state of knowledge of chemokine receptor structure and discusses recent developments toward the determination of the full three-dimensional structure of these important receptors.

The biochemical events that are elicited upon chemokine engagement have been a major focus of interest in many cell types responding to a plethora of different chemokines. We now appreciate that collectively, chemokines can couple to a wide range of biochemical signals including phosphoinositide lipid metabolism, elevation of intracellular calcium levels, and activation of a wide array of protein and lipid kinases as well as small GTPases. Chemokine signaling events are particularly well studied in T lymphocytes where the ordered directional migration of T lymphocytes is a key process in development, immune surveillance, and immune responses. These cells therefore offer a splendid model system in which to understand the array of signals activated by chemokines and their functional importance. One of the most robust biochemical signals elicited by chemokines is the activation of several members of the phosphoinositide 3-kinase (PI3K) family. In many cell systems, PI3Ks are known to contribute to several aspects of the migratory machinery including gradient sensing, signal amplification, actin reorganization and hence cell motility. This chapter will therefore focus on the role of PI3K-dependent signaling events in T-lymphocyte migration and points at which these events may integrate with other effectors and signaling cascades.

Neutrophils are the most abundant leukocytes in circulation. They rapidly infiltrate sites of tissue injury and play a critical role in innate immune responses. In addition, they also contribute to the development of adaptive immune responses. Isolation of the human chemokine IL-8 and the cloning of its receptors CXCR1 and CXCR2, followed by the cloning of their orthologues or homologues in animals, have enabled researchers to elucidate the mechanisms of neutrophil trafficking during immune responses at a molecular level. Since then, there has been tremendous progress in understanding how the trafficking of neutrophils is regulated by the chemokine/chemokine receptor system under not only pathologic but also physiologic conditions. In this chapter, the roles of the chemokine receptors in regulating the trafficking of neutrophils are described.

Dendritic cell (DC) networks dictate peripheral tolerance and immunity in lymph nodes (LNs). The type, timing, location, and interaction of LN-recruited DC subtypes are pivotal and regulated by chemokines. We propose a concept that any DC subtype including myeloid and plasmacytoid DCs (mDCs and pDCs) is fundamentally categorized by three stages depending on the function and anatomical position: naïve DC, primed DC, and effector DC. Naïve mDC precursors are recruited to inflamed tissues in response to CCR1 and CCR5 ligands to become primed mDCs, remobilized to draining LNs in response to CCR7 ligands, and activated to become effector mDCs to undergo antigen-presenting function. In contrast, pDC precursors directly migrate to LNs in a CXCR3-dependent manner. LN-recruited, primed pDCs are activated to become effector pDCs that produce large amounts of cytokines and chemokines. Concerted recruitment and adequate network formation of distinct effector DCs are pivotal to determine the type and efficacy of immune response.

The ordered movement of lymphocytes through and positioning within lymphoid organs and peripheral sites is controlled by adhesion molecules together with chemokines and their receptors. Chemokine-mediated lymphocyte migration is critical for establishing the architecture of lymphoid organs and many aspects of lymphocyte function, including lymphocyte development, activation, and effector activity. Of the 19 chemokine receptors described in humans, all have been reported to be expressed on lymphocytes, and the expression pattern of chemokine receptors can itself be used to define and characterize lymphocyte subsets. For example, by using chemokine receptors, memory T cells can be split into distinct populations, such as central and effector memory T cells; and T helper 1 (Th1) and T helper 2 (Th2) cells exhibit distinguishable patterns of chemokine receptor expression, which can be used to study Th1/Th2 differentiation. Beyond their physiologic roles, chemokine receptors on lymphocytes are exploited by pathogens, such as in the use of CCR5 and CXCR4 by HIV-1 as coreceptors for viral entry. In this chapter, we will focus on the roles of chemokine receptors in lymphocyte trafficking in lymphoid organs and peripheral tissues and how understanding the chemokine system has shed light on larger issues in lymphocyte biology. We will discuss the roles of chemokines and chemokine receptors during the life cycles of lymphocytes—from early development through the acquisition of memory and effector functions.

Chemokines regulate the process of hematopoiesis by controlling trafficking, proliferation/survival, and differentiation of hematopoietic stem and progenitor cells. Unique expression of the chemokine receptor CXCR4 in combination with adhesion molecules [very late antigen (VLA)-4, lymphocyte function-associated antigen-1 (LFA-1), and VLA-5] on early hematopoietic stem and progenitor cells makes their homing to bone marrow and seeding the stem cell niche possible. In bone marrow, the CXCL12-CXCR4 chemokine axis promotes the survival and retention of hematopoietic stem and early progenitor cells. In certain conditions, hematopoietic stem and progenitor cells are released from bone marrow to the blood circulation, a process called mobilization. Many agents that mobilize marrow progenitor cells induce or activate certain proteases of neutrophils. This leads to degradation of CXCL12 and, therefore, weakens the chemotactic activity of bone marrow. Whereas CXCL12 plays a positive role in survival and proliferation of hematopoietic stem and progenitor cells, many other chemokines suppress these processes. During their differentiation into mature cells, hematopoietic progenitor cells upregulate cell lineage-specific chemokine receptors to migrate to appropriate tissue sites. This cell type-specific switch in chemokine receptors and adhesion molecules is important for tissue-specific migration of hematopoietic cells, a process important for their differentiation or effector function in the periphery.

Chemokines exert multiple actions in inflammation, wound healing, and differentiation. Because these processes underlie aspects of the pathophysiology of allograft rejection, chemokine biology has been a major focus of transplantation studies. Although diverse sets of chemokines can be detected in allografts after ischemic reperfusion injury and acute and chronic rejection, recent studies now suggest that relatively few chemokine receptors play central roles in the development of transplant rejection. The antagonism of select chemokine receptors causes a reduction in leukocyte infiltration, prolongs graft function, and can synergize with other immune-suppressive regimens. Chemokine-targeted therapy may represent an important approach in the treatment of allograft rejection.

Rheumatoid arthritis (RA) affects 1% of the U.S. population, or 3 million people. RA is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, neovascularization, and progressive destruction of cartilage and bone. The cause(s) of RA remains poorly defined, but it is thought that both genetic and environmental factors, including molecular mimicry and host responses against cross-reactive antigens, lead to the development of autoimmune responses involving the joints. The goal of this chapter is to provide an overview of the contribution of members of the chemokine system to the immunopathogenesis of RA. This is of high clinical relevance because of the burgeoning interest in the use of chemokine and chemokine-receptor blockers in the treatment of a variety of inflammatory, autoimmune, and infectious disorders, including RA.