Chemokine ligand 18 is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body. CCL18 is produced and secreted mainly by innate immune system, and has effects mainly on the adaptive immune system. It was previously known as Pulmonary and activation-regulated chemokine, dendritic cell -chemokine 1, alternative macrophage activation-associated CC chemokine-1, and macrophage inflammatory protein-4.
The gene of CCL18 is most similar to CCL3. CCL18 is located on chromosome 17, along with many other macrophage inflammatory proteins. The gene itself has 3 exons and 2 introns; but, unlike other chemokines, CCL18 includes 2 pseudo-exons in the first intron. Because of these pseudo-exons, it is believed that CCL18 arose as a result of a gene fusion event between CCL3-like protein encoding genes and gained a different function over time due to accumulating mutations. CCL18 is an 89 amino-acid-long protein, with a 20 amino-acid-long peptide signalling sequence at the N’ terminus which is cleaved in the endoplasmic reticulum into a 69 amino-acid-long mature protein.
Chemotactic functions
s are classed as a special type of cytokine that is involved in immune cell trafficking. CCL18 in particular has some chemotactic functions for the innate immune system, but its functions are primarily involved with recruitment of the adaptive immune system. CCL18 is involved in attracting naïve T-cells, T-regulatory cells, T-helper 2 cells, both immunosuppressive and immature Dendritic Cells, basophils, and B-cells. The T-regulatory cells that CCL18 attracts are not classical T-regulatory cells; these cells do not express FoxP3 as most T-regulatory cells do, and instead non-antigen specifically exert their immunosuppressive functions by secreting IL-10. It is thought that these recruited cells maintain homeostasis under healthy conditions.
Receptor
The classical receptors for chemokines are G-protein coupled receptors Further elucidation of the role of CCR8 in CCL18-mediated pathologies would allow for better understanding of CCL18's function in these diseases.
Effector functions
CCL18 has a plethora of functions that have been characterized in vitro and in vivo. Strangely, CCL18 seems to play a part in both activation of the immune system and the induction of tolerance and homeostasis at steady-state conditions.
Immune activation
The production of CCL18 is induced by T-helper 2 type cytokines, namely IL-4 and IL-13. Coupled with the fact that CCL18 is highly expressed in patients with allergic asthma and other hypersensitivity diseases, CCL18 seems to play an important role for generating and maintaining a T-helper 2 type response. Furthermore, the addition of CCL18 as an adjuvant for a malaria vaccine have shown efficacy, perhaps by recruiting immune cells to the site of vaccination. Finally, CCL18 is expressed by dendritic cells in the germinal center of inflamed lymph nodes, and recruits naïve B-cells for antigen presentation. Perhaps aberrant CCL18 expression is involved in the generation of chronic Th2 response, leading to asthma or arthritis.
Immunosuppression
In addition to immune-activating effects, CCL18 also has strong immunosuppressive effects. CCL18 induces immature dendritic cells to differentiate into an immunosuppressive dendritic cell that is capable producing CCL18 which attract T-cells, suppressing effector T-cell function, and generating T-regulatory cells by secreting large amounts of IL-10. Furthermore, exposure to CCL18 by macrophages causes them to mature in the #M2 spectrum, which promotes immunosuppression and healing.
Involvement in disease
Aberrant CCL18 expression is observed in many diseases, and it is thought that these abnormal expression patterns play a key role in these diseases. This shows a list of all the diseases that CCL18 is involved in.
Breast cancer
The most understood disease that CCL18 is involved in is in breast cancer, where CCL18 induces metastasis of breast cancer cells by binding to PITPNM3. Perhaps CCL18, in breast cancers, is acting as an immunosuppressive cytokine by generating T-regulatory cells, generating immunosuppressive dendritic cells and macrophages, and recruiting effector T-cells to these dendritic cells and macrophages to abolish their anti-cancer functions and allowing the cancer to escape the immune system.
Autoimmunity and hypersensitivity
CCL18 is highly expressed in T-helper 2 mediated hypersensitivity and autoimmune diseases, such as asthma and arthritis. CCL18 is expressed at much higher levels in allergic patients compared to healthy patients and respond aggressively to antigens. Allergic patients also had higher amounts of activated T-cells in the lungs, suggesting that CCL18 recruitment of these cells is contributing to hypersensitivity. In addition to lung hypersensitivities, these patterns were also observed in dermatitis patients. Furthermore, a similar pattern was also observed in arthritis patients, where CCL18 was expressed at much higher rates by dendritic cells in affected patients. However, in arthritis, perhaps the increased CCL18 is an attempt to suppress effector T-helper 1 cells that are self-reactive.
