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Chemokines and Chemokine Receptors

Philip M. Murphy

INTRODUCTION KEY CONCEPTS
Chemokines form a large family composed primarily of small Chemokine and Chemokine Receptors at
secreted cytokine proteins that coordinate leukocyte trafficking a Glance
by binding to seven-transmembrane (7TM) domain receptors.
Chemokines mediate normal host defense and tissue repair; • Definition: Chemokines are defined by a common structure, the
however, they may also support pathological immune responses, chemokine fold. Chemokine receptors are defined by a common
biochemical function: chemokine binding-dependent cell signaling.
including chronic inflammation, autoimmunity, and cancer. The Most chemokine receptors catalyze guanine nucleotide exchange on
chemokine system is also a major target for immune system Gi-type G proteins. A small group of atypical receptors signal through
evasion or exploitation by pathogens (e.g., human immunode- an arrestin-dependent pathway.
ficiency virus [HIV] and Plasmodium vivax). Increasingly, • Classification: Chemokines form four main structural subclasses (C,
additional immunological and nonimmunological chemokine CC, CXC, and CX3C) and two main immunological subclasses (inflam-
matory and homeostatic).
functions are being recognized. The nonimmunological functions • Evolution: Chemokines and chemokine receptors arose in vertebrates
can be beneficial, as in embryogenesis, or harmful, as in cancer. and have been copied or mimicked by viruses. Chemokines and
WHIM (warts, hypogammaglobulinemia, infections, and myelo- chemokine receptors rapidly evolve; the repertoires can differ among
kathexis) syndrome is the only known mendelian condition species and among individuals of the same species.
caused by mutations in a chemokine or chemokine receptor (the • Ligand–receptor promiscuity: The majority of chemokine receptors
receptor CXCR4). Two chemokine receptor antagonists have been pair promiscuously with chemokine ligands, usually restricted to a
approved by the U.S. Food and Drug Administration (FDA) so single chemokine subclass; these typically mediate inflammatory
responses.
far: maraviroc, a CCR5 antagonist, used in the treatment of • Cell biology: Chemokines coordinate leukocyte trafficking but can have
human immunodeficiency virus/acquired immunodeficiency prominent nontrafficking functions (e.g., lymphocyte proliferation/
syndrome (HIV/AIDS), and plerixafor, a CXCR4 antagonist, apoptosis/differentiation/activation, granulocyte degranulation/superoxide
approved for hematopoietic stem cell mobilization for transplanta- production, direct antimicrobial activity), and nonimmunological effects
tion in cancer. This chapter will expand on these and other basic on other cell types (e.g., development, cancer, angiogenesis).
principles and clinical correlates of chemokine regulation of the • Biology: Chemokines act redundantly or nonredundantly in vivo,
immune system. depending on the context. Host chemokine receptors mediate anti-
microbial defense, but certain pathogens (e.g., HIV and Plasmodium
vivax infection) can exploit chemokine receptors to infect the host.
MOLECULAR ORGANIZATION OF THE Excessive or inappropriate chemokine expression may pathologically
CHEMOKINE SYSTEM amplify immunologically mediated disease.

1
Chemokines are defined by structure rather than function. This
reflects the highly conserved nature of their tertiary folded
structure that is created by uniformly spaced, disulfide-bonded Several additional motifs enable subclassification of CC and
cysteines (Fig. 10.1). Chemokines contain three β-sheets arranged CXC chemokines. The seven CXC chemokines with glu-leu-arg
in the shape of a Greek key, overlaid by a C-terminal α-helical (ELR) N-terminal to C-1 share greater than 40% sequence identity,
domain and flanked by an N-terminal domain that lacks order. attract neutrophils, bind the same CXCR2 receptor, and are
All chemokines have at least two cysteines, and all but two have angiogenic (Table 10.1). CXCL9, CXCL10, and CXCL11 share a
at least four. In the four-cysteine group, the first two are either receptor (CXCR3) as well as greater than 40% identity, but they
adjacent (CC motif, n = 24) or separated by either one amino are angiostatic.
acid (CXC motif, n = 16) or three amino acids (CX3C motif, n Two CC subgroups have two additional cysteines. One is in
= 1). Disulfide bonds link C-1 to C-3 and C-2 to C-4. C che- the C-terminal domain, and the other can be found either in
mokines (n = 2) have only two cysteines, corresponding to C-2 the C-terminal domain or between C-2 and C-3 (Table 10.2).
and C-4 in the other groups. Sequence identity is less than 30% CXCL16 and CX3CL1 cross classes to form a unique multimodular
for any two chemokines from different groups but ranges between subgroup. Each has a classic chemokine domain, a mucin-like
30% and 99% for any two chemokines from the same group. stalk, a transmembrane domain, and a C-terminal cytoplasmic
The group names are used as roots followed by the letter “L” module. Each can exist as either a membrane-bound form or a
and a number (e.g., CXCL1) in a systematic nomenclature that shed form, enabling either direct cell–cell adhesion or chemotaxis,
was established to resolve competing aliases. 2 respectively. Chemokine monomer, dimer, and tetramer structures

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