The Chemokine Superfamily: Critical Regulators of Homeostasis & Inflammation

Chemokines are a family of small, secreted, chemotactic cytokines that bind to G protein-coupled receptors to direct cell migration during both homeostatic and inflammatory conditions. They function by forming soluble or immobilized concentration gradients that direct the migration of cells expressing the appropriate chemokine receptors towards areas of high chemokine concentration. Although there are considerable species-specific differences, the chemokine superfamily currently consists of approximately 50 proteins in human and mice combined. These proteins are divided into four subfamilies, based on the number and spacing of conserved cysteine residues located in the amino-terminus. These include the C chemokine, CC chemokine, CXC chemokine, and CX3C chemokine subfamilies. In addition to their subfamily classification, chemokines are also classified based on their functions as inflammatory, homeostatic, or dual-function chemokines. While inflammatory chemokines are induced in response to inflammatory stimuli and promote the rapid recruitment of immune cells to infected tissues to eliminate pathogens, homeostatic chemokines are constitutively expressed and are involved in guiding stem and progenitor cell migration during organ development and wound healing, along with immune cell migration in healthy tissues.

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Chemokines signal by activating conventional chemokine receptors, which are named according to the subfamily of chemokines that they bind (XCR, CCR, CXCR, CX3CR). Activation of these G protein-coupled receptors triggers intracellular signaling pathways that regulate changes in actin polymerization and cytoskeleton rearrangements, focal adhesion assembly and disassembly, and ultimately, cell migration. In addition, chemokine-induced signaling pathways can also promote cell survival, activation, and proliferation. Part of the complexity of the chemokine system is that many chemokine receptors can be activated by more than one ligand. This promiscuity, coupled with the fact that many immune cell types express more than one chemokine receptor, can make it difficult to determine the in vivo role of one chemokine versus another in a specific process or immune response. Adding to the complexity is the fact that there are at least four atypical chemokine receptors that are primarily expressed by non-hematopoietic cell types, which can also bind to a subset of chemokines and function as decoy or scavenger receptors in different cellular contexts. Unlike conventional chemokine receptors, atypical chemokine receptors are unable to activate G protein signaling and are thought to be involved in regulating the resolution of chemokine-driven inflammatory responses.

While chemokines and their receptors play an indispensable role in controlling cell migration during development, homeostatic conditions, and inflammation, they are also associated with numerous pathological conditions. Due to their ability to promote signaling pathways that directly control leukocyte migration and inflammatory responses, inappropriate or unregulated chemokine activity has the potential to drive excessive inflammation, which is characteristic of chronic inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, diabetes, inflammatory bowel disease, atherosclerosis, asthma, and neurodegenerative diseases. In addition, chemokines are involved in regulating anti-tumor immune responses as they control not only the immune cell composition of the tumor microenvironment, but also tumor cell proliferation, metastasis, and tumor-associated angiogenesis. As a result, therapeutic strategies targeting chemokines and chemokine receptors are being actively investigated for the treatment of both chronic inflammatory diseases and cancer.