CCL11 explained

C-C motif chemokine 11 also known as eosinophil chemotactic protein and eotaxin-1 is a protein that in humans is encoded by the CCL11 gene. This gene is encoded on three exons and is located on chromosome 17.^[1]

Function

CCL11 is a small cytokine belonging to the CC chemokine family. CCL11 selectively recruits eosinophils by inducing their chemotaxis, and therefore, is implicated in allergic responses.^{[2] [3] [4]} The effects of CCL11 are mediated by its binding to a G-protein-linked receptor known as a chemokine receptor. Chemokine receptors for which CCL11 is a ligand include CCR2,^[5] CCR3^[6] and CCR5.^[5] However, it has been found that eotaxin-1 (CCL11) has high degree selectivity for its receptor, such that they are inactive on neutrophils and monocytes, which do not express CCR3.^[7]

Clinical significance

Increased CCL11 levels in blood plasma are associated with aging in mice and humans.^[8] Additionally, it has been demonstrated that exposing young mice to CCL11 or the blood plasma of older mice decreases their neurogenesis and cognitive performance on behavioural tasks thought to be dependent on neurogenesis in the hippocampus.

Higher plasma concentrations of CCL11 have been found in current cannabis users compared to past users and those who had never used. CCL11 has also been found in higher concentrations in people with schizophrenia; cannabis is a known trigger of schizophrenia.^[9]

It's also a biomarker for CTE or punch-drunk syndrome.^[10]

During periods of bone inflammation, CCL11 and CCR3 are upregulated. This is associated with an increase in osteoclast activity.^[11]

In 2022, Monje et al demonstrated that elevated levels of CCL11 may contribute to the brain fog associated with both chemotherapy and so-called long covid^{[12] [13]}

Further reading

• Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, Celestin J, Leder P, Luster AD . Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia . Nature Medicine . 2 . 4 . 449–56 . Apr 1996 . 8597956 . 10.1038/nm0496-449 . 25571283 .
• Ponath PD, Qin S, Ringler DJ, Clark-Lewis I, Wang J, Kassam N, Smith H, Shi X, Gonzalo JA, Newman W, Gutierrez-Ramos JC, Mackay CR . Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils . The Journal of Clinical Investigation . 97 . 3 . 604–12 . Feb 1996 . 8609214 . 507095 . 10.1172/JCI118456 .
• Kitaura M, Nakajima T, Imai T, Harada S, Combadiere C, Tiffany HL, Murphy PM, Yoshie O . Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3 . The Journal of Biological Chemistry . 271 . 13 . 7725–30 . Mar 1996 . 8631813 . 10.1074/jbc.271.13.7725 . free .
• Daugherty BL, Siciliano SJ, DeMartino JA, Malkowitz L, Sirotina A, Springer MS . Cloning, expression, and characterization of the human eosinophil eotaxin receptor . The Journal of Experimental Medicine . 183 . 5 . 2349–54 . May 1996 . 8642344 . 2192548 . 10.1084/jem.183.5.2349 .
• Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J . The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates . Cell . 85 . 7 . 1135–48 . Jun 1996 . 8674119 . 10.1016/S0092-8674(00)81313-6 . 16198200 . free .
• Ponath PD, Qin S, Post TW, Wang J, Wu L, Gerard NP, Newman W, Gerard C, Mackay CR . Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils . The Journal of Experimental Medicine . 183 . 6 . 2437–48 . Jun 1996 . 8676064 . 2192612 . 10.1084/jem.183.6.2437 .
• Bartels J, Schlüter C, Richter E, Noso N, Kulke R, Christophers E, Schröder JM . Human dermal fibroblasts express eotaxin: molecular cloning, mRNA expression, and identification of eotaxin sequence variants . Biochemical and Biophysical Research Communications . 225 . 3 . 1045–51 . Aug 1996 . 8780731 . 10.1006/bbrc.1996.1292 .
• Garcia-Zepeda EA, Rothenberg ME, Weremowicz S, Sarafi MN, Morton CC, Luster AD . Genomic organization, complete sequence, and chromosomal location of the gene for human eotaxin (SCYA11), an eosinophil-specific CC chemokine . Genomics . 41 . 3 . 471–6 . May 1997 . 9169149 . 10.1006/geno.1997.4656 .
• Hein H, Schlüter C, Kulke R, Christophers E, Schröder JM, Bartels J . Genomic organization, sequence, and transcriptional regulation of the human eotaxin gene . Biochemical and Biophysical Research Communications . 237 . 3 . 537–42 . Aug 1997 . 9299399 . 10.1006/bbrc.1997.7169 .
• Nibbs RJ, Wylie SM, Yang J, Landau NR, Graham GJ . Cloning and characterization of a novel promiscuous human beta-chemokine receptor D6 . The Journal of Biological Chemistry . 272 . 51 . 32078–83 . Dec 1997 . 9405404 . 10.1074/jbc.272.51.32078 . free .
• Rubbert A, Combadiere C, Ostrowski M, Arthos J, Dybul M, Machado E, Cohn MA, Hoxie JA, Murphy PM, Fauci AS, Weissman D . Dendritic cells express multiple chemokine receptors used as coreceptors for HIV entry . Journal of Immunology . 160 . 8 . 3933–41 . Apr 1998 . 10.4049/jimmunol.160.8.3933 . 9558100 . 7923523 . free .
• Noso N, Bartels J, Mallet AI, Mochizuki M, Christophers E, Schröder JM . Delayed production of biologically active O-glycosylated forms of human eotaxin by tumor-necrosis-factor-alpha-stimulated dermal fibroblasts . European Journal of Biochemistry . 253 . 1 . 114–22 . Apr 1998 . 9578468 . 10.1046/j.1432-1327.1998.2530114.x . free .
• Crump MP, Rajarathnam K, Kim KS, Clark-Lewis I, Sykes BD . Solution structure of eotaxin, a chemokine that selectively recruits eosinophils in allergic inflammation . The Journal of Biological Chemistry . 273 . 35 . 22471–9 . Aug 1998 . 9712872 . 10.1074/jbc.273.35.22471 . free .
• Sabroe I, Hartnell A, Jopling LA, Bel S, Ponath PD, Pease JE, Collins PD, Williams TJ . Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways . Journal of Immunology . 162 . 5 . 2946–55 . Mar 1999 . 10.4049/jimmunol.162.5.2946 . 10072545 . 27211138 . free .
• Jinquan T, Quan S, Feili G, Larsen CG, Thestrup-Pedersen K . Eotaxin activates T cells to chemotaxis and adhesion only if induced to express CCR3 by IL-2 together with IL-4 . Journal of Immunology . 162 . 7 . 4285–92 . Apr 1999 . 10.4049/jimmunol.162.7.4285 . 10201960 . 23620500 . free .
• Klein RS, Williams KC, Alvarez-Hernandez X, Westmoreland S, Force T, Lackner AA, Luster AD . Chemokine receptor expression and signaling in macaque and human fetal neurons and astrocytes: implications for the neuropathogenesis of AIDS . Journal of Immunology . 163 . 3 . 1636–46 . Aug 1999 . 10.4049/jimmunol.163.3.1636 . 10415069 . 23749985 . free .
• Blanpain C, Migeotte I, Lee B, Vakili J, Doranz BJ, Govaerts C, Vassart G, Doms RW, Parmentier M . CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist . Blood . 94 . 6 . 1899–905 . Sep 1999 . 10477718 . 10.1182/blood.V94.6.1899.
• Zhang J, Lathbury LJ, Salamonsen LA . Expression of the chemokine eotaxin and its receptor, CCR3, in human endometrium . Biology of Reproduction . 62 . 2 . 404–11 . Feb 2000 . 10642580 . 10.1095/biolreprod62.2.404 . 28214811 .
• Kampen GT, Stafford S, Adachi T, Jinquan T, Quan S, Grant JA, Skov PS, Poulsen LK, Alam R . Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases . Blood . 95 . 6 . 1911–7 . Mar 2000 . 10706854 . 10.1182/blood.V95.6.1911. 25314791 .
• Huber MA, Kraut N, Addicks T, Peter RU . Cell-type-dependent induction of eotaxin and CCR3 by ionizing radiation . Biochemical and Biophysical Research Communications . 269 . 2 . 546–52 . Mar 2000 . 10708591 . 10.1006/bbrc.2000.2287 .

Notes and References

1. Hein H, Schlüter C, Kulke R, Christophers E, Schröder JM, Bartels J . Genomic organization, sequence, and transcriptional regulation of the human eotaxin gene . Biochemical and Biophysical Research Communications . 237 . 3 . 537–42 . Aug 1997 . 9299399 . 10.1006/bbrc.1997.7169 .
2. Jose PJ, Griffiths-Johnson DA, Collins PD, Walsh DT, Moqbel R, Totty NF, Truong O, Hsuan JJ, Williams TJ . Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation . The Journal of Experimental Medicine . 179 . 3 . 881–7 . Mar 1994 . 7509365 . 2191401 . 10.1084/jem.179.3.881 .
3. Ponath PD, Qin S, Ringler DJ, Clark-Lewis I, Wang J, Kassam N, Smith H, Shi X, Gonzalo JA, Newman W, Gutierrez-Ramos JC, Mackay CR . Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils . The Journal of Clinical Investigation . 97 . 3 . 604–12 . Feb 1996 . 8609214 . 507095 . 10.1172/JCI118456 .
4. Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, Celestin J, Leder P, Luster AD . Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia . Nature Medicine . 2 . 4 . 449–56 . Apr 1996 . 8597956 . 10.1038/nm0496-449 . 25571283 .
5. Ogilvie P, Bardi G, Clark-Lewis I, Baggiolini M, Uguccioni M . Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5 . Blood . 97 . 7 . 1920–4 . Apr 2001 . 11264152 . 10.1182/blood.V97.7.1920 . free .
6. Kitaura M, Nakajima T, Imai T, Harada S, Combadiere C, Tiffany HL, Murphy PM, Yoshie O . Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3 . The Journal of Biological Chemistry . 271 . 13 . 7725–30 . Mar 1996 . 8631813 . 10.1074/jbc.271.13.7725 . free .
7. Baggiolini M, Dewald B, Moser B . Human chemokines: an update . Annual Review of Immunology . 15 . 675–705 . 1997 . 9143704 . 10.1146/annurev.immunol.15.1.675 .
8. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T . 6 . The ageing systemic milieu negatively regulates neurogenesis and cognitive function . Nature . 477 . 7362 . 90–4 . Sep 2011 . 21886162 . 3170097 . 10.1038/nature10357 . 2011Natur.477...90V .
9. Fernandez-Egea E, Scoriels L, Theegala S, Giro M, Ozanne SE, Burling K, Jones PB . Cannabis use is associated with increased CCL11 plasma levels in young healthy volunteers . Progress in Neuro-Psychopharmacology & Biological Psychiatry . 46 . 25–8 . Oct 2013 . 23820464 . 10.1016/j.pnpbp.2013.06.011 . 207410464 .
10. Cherry JD, Stein TD, Tripodis Y, Alvarez VE, Huber BR, Au R, Kiernan PT, Daneshvar DH, Mez J, Solomon TM, Alosco ML, McKee AC . CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer's disease . PLOS ONE . 12 . 9 . e0185541 . 2017 . 28950005 . 5614644 . 10.1371/journal.pone.0185541 . 2017PLoSO..1285541C . free .
    • Web site: Michelle Taylor . 2017-09-28 . Biomarker May Distinguish Between CTE, Alzheimer's During Life . LabEquipment . https://web.archive.org/web/20171016013926/https://www.laboratoryequipment.com/news/2017/09/biomarker-may-distinguish-between-cte-alzheimers-during-life . 2017-10-16.
11. Kindstedt E, Holm CK, Sulniute R, Martinez-Carrasco I, Lundmark R, Lundberg P . CCL11, a novel mediator of inflammatory bone resorption . Scientific Reports . 7 . 1 . 5334 . July 2017 . 28706221 . 5509729 . 10.1038/s41598-017-05654-w . 2017NatSR...7.5334K .
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