Chemokines Regulate Cell Migration Under Homeostatic and Inflammatory Conditions

Chemokine Ligand-Receptor Interactions

Chemokines are a large family of small, secreted or cell surface-localized proteins that bind to seven transmembrane, G protein-coupled receptors and regulate cell migration, including chemotaxis, haptotaxis, chemokinesis, haptokinesis, cell adhesion, and chemorepulsion. Chemokines function by establishing concentration gradients, which are formed either by soluble chemokines or by chemokines immobilized on cell surfaces or in the extracellular matrix due to their interactions with glycosaminoglycans. These chemokine gradients direct the movement of target cells expressing the corresponding chemokine receptor towards areas of high chemokine concentration. This is crucial for the recruitment of immune cells to sites of infection or tissue damage and is also required for directing immune cell trafficking under homeostatic conditions to mediate immune surveillance in healthy tissues. Besides directing cell migration, chemokine signaling has been found to regulate a wide variety of other biological processes in leukocytes, such as cell survival, proliferation, differentiation, degranulation, cytokine production, and phagocytosis. Additionally, chemokines contribute to the regulation of some important processes involving non-immune cell types, such as organogenesis, angiogenesis, and tumor cell trafficking.

Chemokine Subfamilies

The chemokine superfamily is divided into four subfamilies (C, CC, CX₃C, and CXC) based on the spacing between two conserved cysteine residues located in their amino-terminal ends. Intramolecular disulfide bonds formed between these N-terminal cysteine residues and additional conserved cysteine residues located downstream help to establish the tertiary structure of the proteins. Members of each chemokine subfamily bind to conventional chemokine receptors that are named according to the chemokine subfamily that they bind (XCR, CCR, CX3CR, and CXCR). Within each subfamily, there is significant promiscuity, so many chemokine receptors are capable of interacting with more than one chemokine to drive intracellular signaling.

C Chemokines

Chemokines belonging to the C chemokine subfamily, which are also known as gamma-chemokines, have a single N-terminal cysteine residue that forms an intramolecular disulfide bridge with a downstream cysteine residue. In contrast to the other chemokine subfamilies, the C chemokines are missing the first and third conserved cysteine residues that form the second disulfide bridge common to other chemokines. To date, there are only two C chemokine subfamily proteins that have been identified in humans and only one in mice. In humans, these include XCL1 and XCL2, while only XCL1 has been found in mice. Both XCL1 and XCL2 bind to the XCR receptor.

CC Chemokines

The CC chemokines, also known as beta-chemokines, have two adjacent cysteine residues directly next to each other in their amino-terminal ends. Members of this chemokine subfamily bind to one or more of ten different conventional CC chemokine receptors, known as CCRs. CC chemokines act as critical mediators of inflammatory responses due to their ability to promote the migration of multiple different immune cell types, including monocytes, dendritic cells, natural killer cells, and T cells. In addition to binding conventional chemokine receptors, some members of the CC chemokine subfamily bind to the atypical chemokine receptors, D6, DARC, or CCRL1, which are primarily expressed by non-hematopoietic cell types. These atypical receptors are typically unable to activate G protein signaling and have been suggested to play a role in the regulating the resolution of inflammatory responses.

CX3C Chemokines

CX₃CL1 is the only member of the CX₃C chemokine subfamily, which are also known as delta-chemokines. CX₃CL1 has three amino acid residues between its two conserved N-terminal cysteine residues. CX₃CL1 binds to CX₃CR1 and regulates both cell migration and cell adhesion.

CXC Chemokines

The final chemokine subfamily is the CXC chemokines, also known as alpha-chemokines. These chemokines have a single variable amino acid between the two N-terminal cysteine residues. Members of the CXC subfamily are further divided based on the presence or absence of a glutamic acid-leucine-arginine (ELR) motif located immediately upstream of the CXC motif. ELR⁺ CXC chemokines function primarily as neutrophil chemoattractants, while ELR^- CXC chemokines function as lymphocyte chemoattractants. Additionally, ELR⁺ CXC chemokines are potent angiogenic factors, while ELR^- CXC chemokines are angiostatic. CXC chemokines bind to one or more of six different CXC receptors, known as CXCRs, and select members also bind to the atypical chemokine receptors, DARC and CXCR7.

Chemokine Classification Based on Function

In addition to their classification as C, CC, CX₃C, or CXC chemokines, chemokines are also classified based on whether they are homeostatic, inflammatory, or dual-functioning chemokines. Homeostatic chemokines are constitutively expressed under normal physiological conditions and play roles in development and organogenesis, immunosurveillance, and tissue renewal and regeneration. In contrast, inflammatory chemokines are induced in response to inflammatory stimuli and are involved in promoting the migration of immune cells to sites of infection or injury to eliminate pathogens and prevent microbial spread. Some chemokines play a role in both homeostatic and inflammatory processes and thus, have been categorized as dual-function chemokines.

Chemokines and Disease

Although chemokines play essential roles in guiding development, maintaining homeostasis, and promoting inflammation in response to infections or injuries, chemokine signaling is also thought to contribute to the pathogenesis of chronic inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, diabetes, inflammatory bowel disease, atherosclerosis, asthma, and neurodegenerative diseases. Additionally, chemokines have also been suggested to contribute to cancer progression both in terms of promoting the recruitment of pro- or anti-tumor immune cells to the tumor microenvironment and in regulating tumor cell metastasis and tumor-associated angiogenesis. As a result, specific chemokines and chemokine receptors are being investigated as potential therapeutic targets for the treatment of these diseases.

Bio-Techne offers a wide selection of bioactive R&D Systems™ recombinant chemokines for studying chemokine functions, along with antibodies for investigating chemokine and chemokine receptor expression, and single and multianalyte immunoassays for quantifying chemokines or analyzing their effects on other inflammatory mediators.