Chemokines are a large family of small proteins secreted by cells. These signaling molecules belong to the broader category of cytokines, but are specifically named for their ability to induce movement. Chemokines are typically small, with a mass of around 8 to 10 kilodaltons, and they are released into the surrounding environment by various cell types, particularly those involved in the immune system. Their fundamental role is to communicate location and direction, guiding responsive cells to specific sites of interest.
Chemokine Classification and Naming
Chemokines are structurally categorized based on a conserved motif of four cysteine residues near the N-terminus of the protein. The arrangement of the first two cysteine residues determines which of the four main families a chemokine belongs to: CXC, CC, C, or CX3C.
In the CXC family (C-X-C), a single amino acid (‘X’) is positioned between the first two cysteine residues. Members of this group are frequently involved in attracting neutrophils and are often named using the prefix CXCL, such as CXCL8. The CC family (C-C) features two adjacent cysteine residues, and these chemokines predominantly attract monocytes, eosinophils, and basophils.
The two less common families are the C chemokines, which contain only one cysteine residue at the N-terminus, and CX3C chemokines, which have three amino acids separating the first two cysteine residues. The systematic naming convention uses a two-letter prefix followed by a number to denote the ligand (L), such as CCL2 or CXCL12.
Mechanism of Action
The biological function of chemokines is centered on chemotaxis, the directed movement of a cell in response to a chemical substance concentration. Chemokines establish a chemical gradient in the tissue, with the highest concentration closest to the secreting cells. Target cells, typically white blood cells, detect this gradient and move up the concentration slope toward the source.
For a cell to respond, it must possess specific sensors on its surface called chemokine receptors. These receptors belong to the G protein-coupled receptor (GPCR) family, characterized by a structure that spans the cell membrane seven times. The binding of a chemokine to its complementary GPCR initiates a cascade of signals inside the cell.
This activation causes the GPCR to interact with an internal heterotrimeric G protein complex, facilitating the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). The activated G protein then dissociates into its Gα and Gβγ subunits, which propagate the signal to downstream effectors. This internal signaling pathway ultimately leads to the rapid reorganization of the cell’s cytoskeleton, particularly the actin filaments.
The cytoskeletal changes cause the cell to polarize and extend a protrusion, known as a lamellipodium, in the direction of the highest chemokine concentration. This ensures precise and rapid migration to the location where the chemokine was released. The process is tightly regulated, with mechanisms like receptor internalization preventing over-stimulation.
Role in Immune Response and Surveillance
Chemokines regulate the movement and positioning of immune cells, serving a dual purpose in maintaining normal body function and responding to threats. They are broadly categorized as either homeostatic or inflammatory based on their primary role. Homeostatic chemokines are produced consistently and are responsible for the constant circulation and organization of lymphocytes within lymphoid organs.
These constitutive chemokines, such as CCL19 and CCL21, guide T-cells and B-cells to specific zones within the lymph nodes where they can interact with antigen-presenting cells for immune surveillance. The proper positioning of immune cells is fundamental for the development of an effective adaptive immune response.
Inflammatory chemokines are produced only when induced by signals of infection, tissue damage, or inflammation. Their rapid release at the site of injury recruits immune cells, like neutrophils and monocytes, from the bloodstream to the affected tissue. This directed recruitment is a necessary step in the innate immune response, enabling these cells to clear bacteria, remove damaged tissue, and initiate the healing process.
Chemokines in Disease Pathology
The chemokine system contributes to the development and progression of various diseases. In autoimmune disorders, an excessive or misdirected production of inflammatory chemokines leads to the inappropriate and chronic recruitment of immune cells to healthy tissues. For example, the chemokine CCL2 and its receptor CCR2 are implicated in the sustained infiltration of monocytes into joints and tissues, which drives the damaging inflammation seen in conditions like rheumatoid arthritis.
Chemokines also play a significant role in the spread of cancer, known as metastasis. Tumor cells exploit specific chemokine pathways, such as the CXCL12/CXCR4 axis. This hijacking allows the cancer cells to use the chemokine gradient to migrate from the primary tumor site to distant organs that express the corresponding ligand, facilitating colonization and growth.
In infectious diseases, certain pathogens have evolved to manipulate the chemokine system. The Human Immunodeficiency Virus (HIV), for instance, utilizes chemokine receptors to gain entry into target immune cells. Specifically, the virus uses the CCR5 and CXCR4 receptors on the surface of CD4+ T lymphocytes as co-receptors to fuse with the cell membrane and initiate infection.