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Chemokine Signaling Pathways

Click on one of the chemokine subfamilies shown in the Explore Pathways box to see additional information about each subfamily and its members. Refer to the table below the pathway to see the alternate names for each chemokine, their reported receptor binding specificities, and their primary immunoregulatory functions.


Chemokine Signaling Pathways
Chemokine
Chemokine
Chemokine Receptor
Chemokine Receptor
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GDP
GDP
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G Protein
G Protein
Jak
Jak
STAT
STAT
STAT Dimer
STAT Dimer
STAT Dimer
STAT Dimer
Cell Proliferation
Chemotactic Response
Cell Proliferation
Chemotactic Response
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Chemokine
Chemokine
Chemokine
Receptor
Chemokine
Receptor
Chemokine Receptor
Chemokine Receptor
Chemokine Receptor
Chemokine Receptor
beta-Arrestin
beta-Arrestin
Recruitment
Recruitment
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GRK
GRK
G alphai
G alphai
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GTP
GTP
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G beta
G beta
G gamma
G gamma
Receptor Desensitization
Internalization
Degradation
Receptor Desensitization
Internalization
Degradation
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G alphai
G alphai
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GTP
GTP
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Adenylyl
Cyclase
Adenylyl
Cyclase
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ATP
ATP
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cAMP
cAMP
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G beta
G beta
G gamma
G gamma
PLC-beta
PLC-beta
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PIP2
PIP2
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DAG
DAG
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IP3
IP3
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IP3 Receptor
IP3 Receptor
Ca2+
Ca2+
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Calmodulin
Calmodulin
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Calcineurin
Phosphatase
Calcineurin
Phosphatase
NFATC
NFATC
NFATC
NFATC
Cell Motility
Cell Motility
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PKC
PKC
IKK
IKK
I kappa B
I kappa B
NF-kappa B
NF-kappa B
NF-kappa B
NF-kappa B
Cell Survival
Proliferation
Adhesion
Cell Survival
Proliferation
Adhesion
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FAK
FAK
FAK
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FAK
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Paxillin
Paxillin
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p130Cas
p130Cas
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Crk
Crk
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PYK2
PYK2
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Paxillin
Paxillin
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p130Cas
p130Cas
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Crk
Crk
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Actin/Focal Adhesion
Assembly/ Disassembly
Cell Migration
Actin/Focal Adhesion
Assembly/ Disassembly
Cell Migration
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P-Rex1
P-Rex1
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Rac
Rac
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p38
p38
JNK
JNK
PAK
PAK
LIMK
LIMK
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CDC42
CDC42
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WASP
WASP
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Arp2/3
Arp2/3
Regulation of Actin
Cytoskeleton
Cell Migration
Regulation of Actin
Cytoskeleton
Cell Migration
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p101
p101
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p110 gamma
p110 gamma
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PI 3-Kinase
PI 3-Kinase
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Itk
Itk
Itk
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Itk
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Vav
Vav
Vav
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Vav
RhoA
RhoA
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ROCK
ROCK
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MLC
MLC
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PDK-1
PDK-1
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Akt/
PKB
Akt/
PKB
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GSK-3 beta
(Inactive)
GSK-3 beta
(Inactive)
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Bad
Bad
(Inactive)
Bad
(Inactive)
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Bad
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Caspase-9 (Inactive)
Caspase-9 (Inactive)
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Anti-Apoptotic
Signal
Anti-Apoptotic
Signal
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FoxO
FoxO
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FoxO
FoxO
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Cell Survival
Cell Survival
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TSC1/2
(Inactive)
TSC1/2
(Inactive)
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Rheb
Rheb
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GTP
GTP
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mTORC1
mTORC1
p70 S6K
p70 S6K
RPS6
RPS6
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4EBP1
4EBP1
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eIF4E
eIF4E
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eIF4E
eIF4E
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4EBP1
4EBP1
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Protein Synthesis
Protein Synthesis
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IKK
IKK
I kappa B
I kappa B
NF-kappa B
NF-kappa B
Proteasomal
Degradation
Proteasomal
Degradation
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Src
Src
Src
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Src
p85
p85
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p110
p110
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PI 3-Kinase
PI 3-Kinase
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ELMO-1
ELMO-1
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DOCK2
DOCK2
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Rac
Rac
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p38
p38
JNK
JNK
PAK
PAK
LIMK
LIMK
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Itk
Itk
Itk
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Itk
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Vav
Vav
Vav
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Vav
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CDC42
CDC42
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WASP
WASP
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Arp2/3
Arp2/3
Regulation of Actin
Cytoskeleton
Cell Migration
Regulation of Actin
Cytoskeleton
Cell Migration
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RhoA
RhoA
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ROCK
ROCK
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MLC
MLC
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FAK
FAK
FAK
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FAK
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Paxillin
Paxillin
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p130Cas
p130Cas
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Crk
Crk
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Rho
GEFs
Rho
GEFs
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PYK2
PYK2
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Paxillin
Paxillin
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p130Cas
p130Cas
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Crk
Crk
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Actin/Focal Adhesion
Assembly/Disassembly
Cell Migration
Actin/Focal Adhesion
Assembly/Disassembly
Cell Migration
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Shc
Shc
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GRB2
GRB2
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SOS
SOS
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Ras
Ras
Ras
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Ras
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GDP
GDP
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Ras
Ras
Ras
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Ras
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GTP
GTP
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Raf
Raf
MEK1/2
MEK1/2
ERK1/2
ERK1/2
p90 RSK
p90 RSK
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CREB
CREB
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c-Fos
c-Fos
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c-Jun
c-Jun
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Elk-1
Elk-1
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Cell Survival
Proliferation
Migration
Cell Survival
Proliferation
Migration
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Proteasomal
Degradation
Proteasomal
Degradation
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• Also known as the gamma subfamily of chemokines.
• Members have only a single conserved N-terminal cysteine residue, which forms a single disulfide bond with a second conserved cysteine residue located downstream.
• Members include human and mouse XCL1 and human XCL2.
• Both members bind to XCR1.
• See the table below the pathway for additional information on the C chemokine subfamily members.
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• Also known as the beta subfamily of chemokines.
• Members have two conserved N-terminal cysteine residues that are adjacent to each other.
• 27 distinct human and/or mouse proteins belonging to this subfamily have been described (CCL1 – CCL28, where mouse Ccl9/10 are the same protein).
• Members bind to one or more CCR chemokine receptor.
• See the table below the pathway for additional information on the CC chemokine subfamily members including their reported receptor binding specificities and primary immunoregulatory functions.
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• Also known as the alpha subfamily of chemokines.
• Members have two conserved N-terminal cysteine residues that are separated by one amino acid.
• Members are categorized as either ELR+ or ELR-, depending on whether they contain a Glu-Leu-Arg (ELR) motif before the first cysteine of the CXC motif.
• 17 different human and/or mouse proteins belonging to this subfamily have been described (CXCL1 – CXCL17).
• Members bind to one or more CXCR chemokine receptor.
• See the table below the pathway for additional information on the CXC chemokine subfamily members including their reported receptor binding specificities and primary immunoregulatory functions.
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• Also known as the delta subfamily of chemokines.
• Members have two conserved N-terminal cysteine residues that are separated by three amino acids.
• Only a single CX3C chemokine has been identified in both human and mouse: CX3CL1.
• CX3CL1 binds to CX3CR1.
• See the table below the pathway for additional information on CX3CL1.
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Chemokine Signaling Pathways

Overview of Chemokine Signaling Pathways

Chemokines are a large family of small (typically 8-14 kDa), chemoattractant proteins that play a central role in controlling leukocyte migration during development, homeostasis, and inflammation. Following secretion, soluble chemokines or those localized to cell surfaces or the extracellular matrix through their interactions with glycosaminoglycans, establish concentration gradients that direct the migration of cells expressing their cognate receptors. To date, approximately 50 human and/or mouse chemokines have been identified. This group of proteins has been further divided into four subfamilies known as the C chemokines, CC chemokines, CXC chemokines, and CX3C chemokines, based on the number and spacing of conserved cysteine residues located in the amino-terminus. While there are considerable species-specific differences in the members of these subfamilies in mice and humans, 2 C chemokine subfamily members (XCL1 and XCL2), 27 CC chemokine subfamily members (CCL1-CCL28, where mouse Ccl9/10 is the same protein), 17 CXC chemokine subfamily members (CXCL1-CXCL17), and 1 CX3C subfamily member (CX3CL1) have been described in these two species combined. In addition to their subfamily classification, chemokines are classified as either homeostatic or inflammatory based on their expression patterns and functions. Homeostatic chemokines are constitutively produced and function in stem, progenitor, or immune cell trafficking during development and in normal steady-state conditions, while inflammatory chemokines are induced in response to inflammatory stimuli and mediate immune cell trafficking in response to infection or tissue damage.

Chemokines activate their target cells by signaling through seven transmembrane G protein-coupled receptors (GPCRs). To date, 18 conventional chemokine receptors have been identified including 1 C chemokine subfamily receptor (XCR1), 10 CC chemokine subfamily receptors (CCR1-CCR10), 6 CXC chemokine subfamily receptors (CXCR1-CXCR6), and 1 CX3C chemokine subfamily receptor (CX3CR1). Within these subfamilies, many chemokines can bind to more than one receptor and many chemokine receptors can be activated by more than one ligand. This promiscuity, coupled with the fact that different immune cell types typically express more than one chemokine receptor, makes the chemokine system particularly complex in terms of delineating the functional significance of one chemokine versus another in different processes. Additionally, chemokines activate multiple downstream signaling pathways, which can vary somewhat depending on the chemokine, the receptor that it activates, and the target cell type. The graphic shows the pathways that chemokines generally activate and is not tailored to any specific chemokine, receptor, or target cell.

Chemokine signaling is initiated following ligand-receptor binding and activation of the receptor-associated, heterotrimeric Gi-type G protein by GDP/GTP exchange, which leads to dissociation of the G alphai and G beta-gamma subunits. The G beta-gamma subunits activate Class 1B PI 3-Kinase and PLC-beta (PLC). Class 1B PI 3-Kinase, consisting of a p101 regulatory subunit and a p110 gamma catalytic subunit, subsequently phosphorylates and activates multiple substrates including Itk and Akt, which regulate downstream signaling pathways that promote cytoskeleton rearrangements, cell survival, cell growth, and proliferation. Concurrently, PLC hydrolyzes PIP2 to produce inositol-triphosphate (IP3) and diacylglycerol (DAG), which trigger calcium mobilization and Protein kinase C (PKC) activation, respectively. Activation of PKC results in the phosphorylation of IKK, which then phosphorylates I kappa B, promoting its ubiquitin-dependent proteasomal degradation, and allowing NF-kappa B to translocate to the nucleus and induce gene expression. PKC also phosphorylates Focal adhesion kinase (FAK) and Proline-rich tyrosine kinase 2 (PYK2), two non-receptor protein tyrosine kinases. These two kinases phosphorylate substrates such as p130Cas and Paxillin to promote focal adhesion formation and disassembly, cytoskeletal reorganization, and cell migration. At the same time as the G beta-gamma subunits activate these intracellular signaling pathways, the G alphai-GTP-bound subunit of the dissociated G protein inhibits adenylyl cyclase, decreasing intracellular cAMP, and stimulates the kinase activity of Src. Src subsequently phosphorylates multiple downstream substrates including Class IA PI 3-Kinase, Itk, FAK, PYK2, ELMO-1, and Shc. While Itk, FAK, and PYK2 are involved in regulating cytoskeletal reorganization and/or focal adhesion formation as previously described, phosphorylation of ELMO-1 by Src activates signaling pathways that promote cytoskeletal rearrangements required for cell motility. In addition, Src-dependent Shc phosphorylation leads to the recruitment of the GRB2-SOS complex and activation of Ras-MAPK signaling pathways, which mediate cell survival, proliferation, and migration. Along with the intracellular pathways activated by the GTP-bound G alphai and G beta-gamma subunits, chemokine-receptor binding also directly activates the Jak-STAT pathway, which promotes changes in cellular polarization that are required for chemotactic responses.

While chemokines play an essential role in directing cell migration, chemokines and chemokine receptors are also associated with a diverse array of pathological conditions. Due to their abilities to control leukocyte trafficking and inflammatory responses, high chemokine expression levels or unregulated chemokine signaling has the potential to drive excessive or persistent inflammation that is characteristic of chronic inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, multiple sclerosis, diabetes, inflammatory bowel disease, atherosclerosis, asthma, and COPD. Additionally, chemokines are involved in regulating anti-tumor immunity not only by regulating the immune cell composition of the tumor microenvironment, but also by regulating tumor cell proliferation and metastasis. As a result, chemokines and chemokine receptors are being actively investigated as therapeutic targets for the treatment of cancer and inflammatory diseases.

To learn more, please visit our Chemokines and Receptors Research Area page.

 

C Chemokine Family
Chemokine Alternate Name(s)  Receptor(s) Primary Immunoregulatory Functions
XCL1 Lymphotactin 1; SCM-1α; ATAC; SCYC1 XCR1 Antigen cross-presentation by CD8+ dendritic cells
XCL2 (human only) Lymphotactin 2; SCM-1β; SCYC2 XCR1
CC Chemokine Family
Chemokine Alternate Name(s)  Receptor(s) Primary Immunoregulatory Functions
CCL1 I-309; TCA3 CCR8 Th2 cell and regulatory T cell trafficking
CCL2 MCP-1; JE (mouse) CCR2, CCR5 Inflammatory monocyte trafficking
CCL3 MIP-1α; LD78α CCR1, CCR4, CCR5 Monocyte, macrophage, natural killer cell migration; Dendritic cell - T cell interactions
CCL4 MIP-1β CCR1, CCR3, CCR5; CCR8 (human only) Monocyte, macrophage, natural killer cell migration; Dendritic cell - T cell interactions
CCL5 RANTES CCR1, CCR3, CCR4, CCR5 Monocyte, macrophage, natural killer cell migration; Dendritic cell - T cell interactions
Ccl6 (mouse only) Mrp-1; c10  Ccr1, Ccr3 Unknown
CCL7 MCP-3; Marc or Fic (mouse) CCR1, CCR2, CCR3 Monocyte mobilization
CCL8 MCP-2 CCR1, CCR2, CCR3, CCR5 (human only); CCR8 (mouse only) Th2 immune response; Skin homing (mouse)
Ccl9/10 (mouse only) MIP-1γ; Mrp-2; Ccf18 Ccr1, Ccr3 Unknown
CCL11 Eotaxin CCR3; CCR5 (human only) Basophil and eosinophil migration
Ccl12 (mouse only) MCP-5 Ccr2 Inflammatory monocyte trafficking
CCL13 (human only) MCP-4; NCC-1 CCR1, CCR2, CCR3, CCR5 Th2 immune response
CCL14 (human only) HCC-1; NCC-2 CCR1, CCR5 Unknown
CCL15 (human only) MIP-1δ; HCC-2; MIP-5; NCC-3; Leukotactin CCR1, CCR3 Unknown
CCL16 (human only) HCC-4; NCC-4; LEC;
MTN-1
CCR1, CCR2, CCR3, CCR5, CCR8 Unknown
CCL17 TARC CCR4; CCR8 (human only) Th2 immune response; Th2 cell migration; regulatory T cell trafficking
CCL18 (human only) PARC; MIP-4; AMAC-1; DC-CK1 CCR8  Th2 immune response; Hematopoiesis; Dendritic cell recruitment of T and B cells for antigen presentation
CCL19 MIP-3β; ELC; Exodus-3 (mouse) CCR7 Dendritic cell and T cell homing to the lymph nodes
CCL20 MIP-3α; LARC; Exodus CCR6 Th17 immune response; Homing of B cells and dendritic cells to gut-associated lymphoid tissue 
CCL21 6CKine; SLC; TCA4 CCR7 Dendritic cell and T cell homing to the lymph nodes
CCL22 MDC CCR4 Th2 immune response; Th2 cell and regulatory T cell migration
CCL23 (human only) CKβ-8; MPIF-1; MIP-3 CCR1 Unknown
CCL24 CKβ-6; MPIF-2; Eotaxin-2 CCR3 Basophil and eosinophil migration
CCL25 TECK; CKβ-15 CCR9 Thymocyte migration; Homing of memory T cell to the gut
CCL26 IMAC; MIP-4α; Eotaxin-3 CCR3; CX3CR1 Basophil and eosinophil migration
CCL27 CTACK CCR10 Homing of T cells to the skin
CCL28 MEC; CCK1 CCR10; CCR3 (human only) Homing of T cells and IgA plasma cells to mucosal surfaces
CXC Chemokine Family
Chemokine Alternate Name(s)  Receptor(s) Primary Immunoregulatory Functions
CXCL1 GROα; MGSA; NAP-3; KC (mouse) CXCR2 Neutrophil trafficking
CXCL2 GROβ; CINC-2a; MIP-2α CXCR2
CXCL3 GROγ; CINC-2b; MIP-2β CXCR2
CXCL4 PF4 CXCR3 Procoagulant
CXCL5 ENA-78; LIX (mouse) CXCR1, CXCR2 Neutrophil trafficking
CXCL6 (human only) GCP-2 CXCR1, CXCR2
CXCL7 NAP-2; PBP CXCR2
CXCL8 (human only) IL-8; GCP-1  CXCR1, CXCR2
CXCL9 MIG CXCR3 Th1 immune response; Natural killer cell, CD8+ T cell, and Th1 cell trafficking
CXCL10 IP-10; CRG-2 CXCR3
CXCL11 I-TAC; IP-9 CXCR3
CXCL12 SDF-1 CXCR4 Bone marrow homing; Myelopoiesis; B lymphopoiesis
CXCL13 BCA-1; BLC CXCR5; CXCR3 (human only) B cell and follicular helper T (Tfh) cell positioning in lymphoid tissue
CXCL14 BRAK; MIP-2γ Unknown Macrophage migration (human)
Cxcl15 (mouse only) Lungkine Unknown Unknown
CXCL16  SRPSOX CXCR6 Migration and survival of natural killer T (NKT) cells and innate lymphoid cells (ILCs)
CXCL17 VCC-1 Unknown Dendritic cell and monocyte chemotaxis
CX3C Chemokine Family
Chemokine Alternate Name(s)  Receptor(s) Primary Immunoregulatory Functions
CX3CL1 Fractalkine; Neurotactin CX3CR1 Monocyte, macrophage, natural killer cell, and Th1 cell migration
Note: Receptors listed in the table are for both the human and mouse chemokines, unless otherwise indicated.