CCR9 explained

C-C chemokine receptor type 9 is a protein that in humans is encoded by the CCR9 gene.^{[1] [2]} This gene is mapped to the chemokine receptor gene cluster region. Two alternatively spliced transcript variants have been described.

CCR9 has also recently been designated CDw199 (cluster of differentiation w199).

The protein encoded by this gene is a member of the beta chemokine receptor family. CCR9 is a seven transmembrane protein similar to G protein-coupled receptors.^{[3] [4] [5]}

Function

Chemokines and their receptors, such as CCR9 and its binding agonist, are key regulators of thymocyte migration and maturation in normal and inflammatory conditions. The specific agonist or ligand that binds CCR9 is CCL25 also referred to as TECK^[6] in some literature. The effects of chemokines binding to their specific receptors is generally dependent on the structural placement of the N terminal cysteine(s) amino acids.^[7] Receptors are broken down into 4 family groups CXC, CC, C, and CX3C, because CCR9 has two adjacent cysteines it is a C-C family receptor. C-C family chemokines (such as CCL25) are often associated with the recruitment of lymphocytes. It has been found that this gene is differentially expressed by T lymphocytes of small intestine and colon, suggesting a role in thymocyte recruitment and development that may permit functional specialization of immune responses in different segments of the gastrointestinal tract.

Clinical significance

The breadth of effects following interactions of CCR9 and its binding ligand CCL25 are vast and not completely understood, however, it is generally thought that CCR9 and CCL25 play substantial roles in cancer proliferation and inflammatory diseases. The location of CCR9 and CCL25 expression plays a substantial role in how it contributes to diseases. For example, the high expression of CCL25 in the epithelial lining of the small intestine, has contributed to its strong association and influence on inflammatory disease of the gut such as inflammatory bowel disease. However, CCR9 and CCL25 have also been associated with other inflammatory conditions such as cardiovascular disease, rheumatoid arthritis, and asthma.^[8] The role of CCR9 in cancer lies primarily in its ability to upregulate cell proliferation, metastasis, and the drug resistance.

Inflammatory Bowel Disease (IBD)

CCR9/CCL25 interactions are known to contribute to the up-regulated migration of memory T cell homing to the gut given high expression of CCL25 in intestinal lining.  As a result, it is suggested that CCR9 and CCL25 have been a key focus in promoting a balanced pro-inflammatory and anti-inflammatory response in the gut. It has been observed that decreased expression of CCL25 and CCR9 contributes to macrophage recruitment in the gut as well as inflammatory cytokines which induces the observed inflammation in IBD. The inflammatory cytokines upregulated in the immune response of IBD are TNF-α, IFN-γ, IL-2, IL-6, IL-17A, and Th1/Th17. Overall, it is likely that the interactions of CCR9 and CCL25 provide substantial protections against large intestinal inflammation via its ability to regulate inflammation in the gut by balancing the presence of inflammatory cytokines.

Myocardial Infarction (MI)

CCR9/CCL25 interaction reduction is believed to improve the survival rate, cardiac function, and reduce infarct size following myocardial infarctions. Additionally, reduced CCR9 expression following myocardial infarctions is also believed to attenuate apoptosis in the cells of the affected cardiac tissue while also reducing inflammation through the down-regulation of inflammatory cytokines including: IL-1β, IL-6, and TNF-α. Overall, CCR9 and CCL25 are believed to play a key role in mitigating the damage to cardiac tissue following heart attacks, while also aiding cardiac remodeling. The role CCR9 and CCL25 is thought to have in cardiovascular health has made it a key area of focus in clinical research.

Cancer

CCR9/CCL25 interaction is believed to significantly influence the cellular functions of cancer cells and ultimately contribute to their proliferation and metastasis. CCR9 and CCL25 interactions are understood to suppress apoptosis observed by cancer cells. Apoptosis in cancer cells is  an essential mechanism utilized to mitigate the proliferation of cancer cells. The suggested reduction in apoptosis observed in cancer cells as a result of CCR9 and CCL25 interactions, ultimately supports the proliferation and metastasis of cancer cells. The observed proliferative and antiapoptotic effects of CCR9/CCL25 interaction, suggests the potential for targeted therapies that down-regulate CCR9/CCL25 for certain cancers including: leukemia, prostate cancer, breast cancer, ovarian cancer and lung cancer.

Further reading

• Youn BS, Kim CH, Smith FO, Broxmeyer HE . TECK, an efficacious chemoattractant for human thymocytes, uses GPR-9-6/CCR9 as a specific receptor . Blood . 94 . 7 . 2533–2536 . October 1999 . 10498628 . 10.1182/blood.V94.7.2533.419k37_2533_2536 .
• Zabel BA, Agace WW, Campbell JJ, Heath HM, Parent D, Roberts AI, Ebert EC, Kassam N, Qin S, Zovko M, LaRosa GJ, Yang LL, Soler D, Butcher EC, Ponath PD, Parker CM, Andrew DP . 6 . Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis . The Journal of Experimental Medicine . 190 . 9 . 1241–1256 . November 1999 . 10544196 . 2195678 . 10.1084/jem.190.9.1241 .
• Wurbel MA, Philippe JM, Nguyen C, Victorero G, Freeman T, Wooding P, Miazek A, Mattei MG, Malissen M, Jordan BR, Malissen B, Carrier A, Naquet P . 6 . The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9 . European Journal of Immunology . 30 . 1 . 262–271 . January 2000 . 10602049 . 10.1002/1521-4141(200001)30:1<262::AID-IMMU262>3.0.CO;2-0 . free .
• Yu CR, Peden KW, Zaitseva MB, Golding H, Farber JM . CCR9A and CCR9B: two receptors for the chemokine CCL25/TECK/Ck beta-15 that differ in their sensitivities to ligand . Journal of Immunology . 164 . 3 . 1293–1305 . February 2000 . 10640743 . 10.4049/jimmunol.164.3.1293 . free .
• Maho A, Bensimon A, Vassart G, Parmentier M . Mapping of the CCXCR1, CX3CR1, CCBP2 and CCR9 genes to the CCR cluster within the 3p21.3 region of the human genome . Cytogenetics and Cell Genetics . 87 . 3–4 . 265–268 . 2000 . 10702689 . 10.1159/000015443 . 1178132 .
• Kunkel EJ, Campbell JJ, Haraldsen G, Pan J, Boisvert J, Roberts AI, Ebert EC, Vierra MA, Goodman SB, Genovese MC, Wardlaw AJ, Greenberg HB, Parker CM, Butcher EC, Andrew DP, Agace WW . 6 . Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity . The Journal of Experimental Medicine . 192 . 5 . 761–768 . September 2000 . 10974041 . 2193265 . 10.1084/jem.192.5.761 .
• Papadakis KA, Prehn J, Nelson V, Cheng L, Binder SW, Ponath PD, Andrew DP, Targan SR . 6 . The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system . Journal of Immunology . 165 . 9 . 5069–5076 . November 2000 . 11046037 . 10.4049/jimmunol.165.9.5069 . free .
• Papadakis KA, Landers C, Prehn J, Kouroumalis EA, Moreno ST, Gutierrez-Ramos JC, Hodge MR, Targan SR . 6 . CC chemokine receptor 9 expression defines a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Th1 or T-regulatory 1 cytokine profile . Journal of Immunology . 171 . 1 . 159–165 . July 2003 . 12816994 . 10.4049/jimmunol.171.1.159 . free .
• Qiuping Z, Qun L, Chunsong H, Xiaolian Z, Baojun H, Mingzhen Y, Chengming L, Jinshen H, Qingping G, Kejian Z, Zhimin S, Xuejun Z, Junyan L, Jinquan T . 6 . Selectively increased expression and functions of chemokine receptor CCR9 on CD4+ T cells from patients with T-cell lineage acute lymphocytic leukemia . Cancer Research . 63 . 19 . 6469–6477 . October 2003 . 14559839 .
• Singh S, Singh UP, Stiles JK, Grizzle WE, Lillard JW . Expression and functional role of CCR9 in prostate cancer cell migration and invasion . Clinical Cancer Research . 10 . 24 . 8743–8750 . December 2004 . 15623660 . 10.1158/1078-0432.CCR-04-0266 . free .
• Babu S, Blauvelt CP, Kumaraswami V, Nutman TB . Chemokine receptors of T cells and of B cells in lymphatic filarial infection: a role for CCR9 in pathogenesis . The Journal of Infectious Diseases . 191 . 6 . 1018–1026 . March 2005 . 15717282 . 10.1086/427658 . free .
• Nagakubo D, Jin Z, Hieshima K, Nakayama T, Shirakawa AK, Tanaka Y, Hasegawa H, Hayashi T, Tsukasaki K, Yamada Y, Yoshie O . 6 . Expression of CCR9 in HTLV-1+ T cells and ATL cells expressing Tax . International Journal of Cancer . 120 . 7 . 1591–1597 . April 2007 . 17205512 . 10.1002/ijc.22483 . 23891689 . free .
• Olaussen RW, Karlsson MR, Lundin KE, Jahnsen J, Brandtzaeg P, Farstad IN . Reduced chemokine receptor 9 on intraepithelial lymphocytes in celiac disease suggests persistent epithelial activation . Gastroenterology . 132 . 7 . 2371–2382 . June 2007 . 17570212 . 10.1053/j.gastro.2007.04.023 . free .

External links

• • Web site: Chemokine Receptors: CCR9 . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-03 . 2008-06-07 . https://web.archive.org/web/20080607150558/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2236 . dead .

Notes and References

1. Zaballos A, Gutiérrez J, Varona R, Ardavín C, Márquez G . Cutting edge: identification of the orphan chemokine receptor GPR-9-6 as CCR9, the receptor for the chemokine TECK . Journal of Immunology . 162 . 10 . 5671–5675 . May 1999 . 10229797 . 10.4049/jimmunol.162.10.5671 . 21522407 . free .
2. Web site: Entrez Gene: CCR9 chemokine (C-C motif) receptor 9.
3. Schulz O, Hammerschmidt SI, Moschovakis GL, Förster R . Chemokines and Chemokine Receptors in Lymphoid Tissue Dynamics . Annual Review of Immunology . 34 . 1 . 203–242 . May 2016 . 26907216 . 10.1146/annurev-immunol-041015-055649 . free .
4. Griffith JW, Sokol CL, Luster AD . Chemokines and chemokine receptors: positioning cells for host defense and immunity . Annual Review of Immunology . 32 . 1 . 659–702 . 2014-03-21 . 24655300 . 10.1146/annurev-immunol-032713-120145 . 10579265 . free .
5. Tu Z, Xiao R, Xiong J, Tembo KM, Deng X, Xiong M, Liu P, Wang M, Zhang Q . 6 . CCR9 in cancer: oncogenic role and therapeutic targeting . Journal of Hematology & Oncology . 9 . 1 . 10 . February 2016 . 26879872 . 4754913 . 10.1186/s13045-016-0236-7 . free .
6. Youn BS, Yu KY, Oh J, Lee J, Lee TH, Broxmeyer HE . Role of the CC chemokine receptor 9/TECK interaction in apoptosis . Apoptosis . 7 . 3 . 271–276 . June 2002 . 11997671 . 10.1023/A:1015320321511 . 25082118 .
7. Wu X, Sun M, Yang Z, Lu C, Wang Q, Wang H, Deng C, Liu Y, Yang Y . 6 . The Roles of CCR9/CCL25 in Inflammation and Inflammation-Associated Diseases . Frontiers in Cell and Developmental Biology . 9 . 686548 . 2021-08-19 . 34490243 . 8416662 . 10.3389/fcell.2021.686548 . free .
8. 6 . Xu B, Deng C, Wu X, Ji T, Zhao L, Han Y, Yang W, Qi Y, Wang Z, Yang Z, Yang Y . December 2020 . CCR9 and CCL25: A review of their roles in tumor promotion . Journal of Cellular Physiology . 235 . 12 . 9121–9132 . 10.1002/jcp.29782 . 32401349. 218617059 .