Chemokines are small signaling proteins that trigger chemotaxis (migratory movement) of cells. In most cases, these cells are immune cells. Thus, chemokines are responsible for the effective functioning of the immune system.
What are chemokines?
Chemokines are small proteins that belong to the cytokine family. They cause cells to migrate. Mainly, these are immune cells that need to quickly reach the appropriate site of injury or infection. The chemokines are produced by the cells which they are also intended to attract. On the surface of these cells there are receptors that enable the chemokines to dock. The signal molecules are divided into inflammatory and homeostatic chemokines. In most cases, they are inflammatory chemokines. They attract immune cells to the destination, which immediately trigger inflammatory processes there to defend against infection. Inflammatory chemokines are always produced at the site of injury or infection by the immune cells present there to attract further defense cells. Homeostatic chemokines are constantly produced, even in the absence of infection. They serve to monitor healthy tissue. Chemokines have a chemotaxic effect on such immune cells as monocytes, macrophages, keratinocytes, fibroblasts, platelets, endothelial cells, T cells, stomatal cells, neutrophilic granulocytes, and dendritic cells. They are also produced as signaling substances by these cells to attract like cells when needed.
Anatomy and structure
Chemokines are small protein chains of 75 to 125 amino acids each. At the terminal end of the chain are one or two cysteine residues. Cysteine is a sulfur-containing amino acid that can form disulfide bridges in the molecule. The cysteine residues now form sulfide bridges within the protein chain. However, while the amino acid sequence is variable within the chemokine family proteins, the tertiary structure remains the same for all chemokines. The main body is formed as a three-stranded antiparallel leaflet with beta structure. At the carboxy terminus, the chain ends with an alpha helix. This is where the cysteine residues are now located. There are four structures how these terminal cysteine residues can be arranged. Each structure symbolizes a family of chemokines. Thus, two cysteine residues can follow directly behind each other. The corresponding chemokine family is called the CC family. If another amino acid is switched between the cysteine residues, it is the CXC family. The CX3C family contains two cysteine residues separated by three amino acids. Finally, there is a family with one cysteine residue, which is called the C family. All cysteine residues form a sulfide bridge within the chain. The individual chemokine families have different functions. The exact structure of the chemokines is still not fully understood. The chemokines do not necessarily require tissue fluid or blood to perform their function. They can also transmit their signals through solid structures by concentration gradients. In doing so, they bind with the positive charge of their many basic amino acids to a negatively charged sugar molecule (glycosaminoglucan) on the surface of cells. Why they lose their function when they can no longer bind to glycosaminoglucan is not yet clear.
Function and tasks
The main function of chemokines is to attract specific immune cells to sites in the body that are currently subject to a higher level of defense against infectious invaders. This makes the immune response more effective. In most cases, they thus also ensure that significant inflammatory responses develop to fight off the infection. They are generated at the site of injury or infection by the immune cells already present there. The now attracted cells move towards the highest concentration of chemokines. The corresponding chemokine receptors are located on their surface. The chemokines bind to these receptors, triggering migration of the cells toward the highest concentration of chemokines. However, each chemokine family binds to its own receptors. For example, the CC family ensures the migration of monocytes, lymphocytes, and basophilic and eosinophilic granulocytes. The CXC family is responsible for angiogenesis (growth of blood vessels). The CX3C family plays a role in inflammatory processes of the nervous system.Finally, C-chemokines activate CD8 T cells and NK cells (natural killer cells).
Diseases
When the interplay between chemokines and chemokine receptors is disturbed, the immune system malfunctions. Often, due to a mutation of the corresponding receptor, it is no longer a good fit for the docking of chemokines. This means that immune cells can no longer be attracted in decisive situations. This malfunction then manifests itself as an immune deficiency. For example, the so-called WHIM syndrome, a specific immune deficiency, is due to a chemokine receptor defect. This disease manifests itself in recurrent viral and bacterial infections. Patients show a particular susceptibility to human papillomavirus, the infection of which manifests itself in the formation of warts. The bone marrow is full of T-precursor cells, but these do not migrate to the sites of infection. Selective immune deficiencies against certain pathogens are also possible. For example, mutation of a receptor for a chemokine of the CC family results in specific susceptibilities to West Nile virus. However, the same receptor, when mutated, also provides hereditary immunity to HIV. Certain mutations in the chemokine receptor region can also be partly responsible for autoimmune diseases or allergies. The overproduction of certain chemokines can also lead to diseases. For example, the development of psoriasis has been found to be related to overproduction of the CXC chemokine IL-8. Rheumatoid arthritis also occurs together with an overproduction of IL-8. Atherosclerotic changes are often the result of excessive inflammatory processes, sometimes caused by increased chemokine activities.
