C-C chemokine receptor type 6

Function

This protein belongs to family A of G protein-coupled receptor superfamily. The gene is expressed in lymphatic and non-lymphatic tissue as spleen, lymph nodes, pancreas, colon, appendix, small intestine. CCR6 is expressed on B-cells, immature dendritic cells (DC), T-cells (Th1, Th2, Th17, Treg), natural killer T cells (NKT cells) and neutrophils. The ligand of this receptor is CCL20 or in the other name - macrophage inflammatory protein 3 alpha (MIP-3 alpha). This chemokine receptor is special because it binds only one chemokine ligand CCL20 in comparison to other chemokine receptors. CCR6 has a key role between immature DC and adaptive immunity. This receptor has been shown to be important for B-lineage maturation and antigen-driven B-cell differentiation, and it may regulate the migration and recruitment of dendritic cells and T cells during inflammatory and immunological responses. Alternatively spliced transcript variants that encode the same protein have been described for this gene.

Interleukin 4 (IL-4) and interferon gamma (IFNγ) suppress expression of CCR6 in langerhans cells development and interleukin 10 (IL-10) induces the expression. It can regulate immune response in inflammatory tissue.

Proinflammatory Th17 cells express CCR6 and its ligand CCL20. CCR6 influences their migration to sites of inflammation. Some Th17 cells migrate via chemokine gradient of CCL20 to inflammatory sites and themselves can express more CCL20 to bring in more Th17 cells and regulatory T-cells (Treg). This can lead to chronic inflammation. In some models, the lack of CCR6 leads to less severe autoimmune encephalomyelitis.

Clinical significance

CCR6 has a function in development and metastatic spread of gastrointestinal malignancies. Expression of CCR6 was found to be up-regulated in colorectal cancer. Many patients with colorectal cancer have liver metastases. Colorectal carcinoma cells express CCR6 and CCL20. High level of CCL20 in liver chemoattract colorectal carcinoma cells and cause metastases in liver. Novel research has identified a microRNA that is able to downregulate CCR6 in cancer cell lines.

CCR6 has been associated with Crohn's disease.

References

References

1. (October 1996). "Molecular cloning and RNA expression of two new human chemokine receptor-like genes". Biochemical and Biophysical Research Communications.
2. (October 2003). "The CC chemokine CCL20 and its receptor CCR6". Cytokine & Growth Factor Reviews.
3. (January 2016). "Chemokine/chemokine receptor pair CCL20/CCR6 in human colorectal malignancy: An overview". World Journal of Gastroenterology.
4. (July 1998). "Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites". The Journal of Experimental Medicine.
5. "Entrez Gene: CCR6 chemokine (C-C motif) receptor 6".
6. (November 2001). "IL-10 induces CCR6 expression during Langerhans cell development while IL-4 and IFN-gamma suppress it". Journal of Immunology.
7. (December 2008). "CCR6 regulates the migration of inflammatory and regulatory T cells". Journal of Immunology.
8. (February 2014). "Chemokine receptor CCR6 expression is regulated by miR-518a-5p in colorectal cancer cells". Journal of Translational Medicine.
9. (September 2013). "CCR6/CCL20 chemokine expression profile in distinct colorectal malignancies". Scandinavian Journal of Immunology.
10. (February 2014). "Chemokine receptor CCR6 expression is regulated by miR-518a-5p in colorectal cancer cells". Journal of Translational Medicine.
11. (March 2009). "Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease". American Journal of Human Genetics.