CHI3L1 explained

Chitinase-3-like protein 1 (CHI3L1), also known as YKL-40, is a secreted glycoprotein that is approximately 40kDa in size that in humans is encoded by the CHI3L1 gene.^{[1] [2] [3]} The name YKL-40 is derived from the three N-terminal amino acids present on the secreted form and its molecular mass. YKL-40 is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells, vascular smooth muscle cells, and hepatic stellate cells. The biological function of YKL-40 is unclear. It is not known to have a specific receptor. Its pattern of expression is associated with pathogenic processes related to inflammation, extracellular tissue remodeling, fibrosis and solid carcinomas^[4] and asthma.^[5]

Function

Chitinases catalyze the hydrolysis of chitin, which is an abundant glycopolymer found in insect exoskeletons and fungal cell walls. The glycoside hydrolase 18 family of chitinases includes eight human family members. This gene encodes a glycoprotein member of the glycosyl hydrolase 18 family. The protein lacks chitinase activity and is secreted by activated macrophages, chondrocytes, neutrophils and synovial cells. The protein is thought to play a role in the process of inflammation and tissue remodeling.^[3] YKL-40 lacks chitinase activity due to mutations within the active site (conserved sequence: DXXDXDXE; YKL-40 sequence: DGLDLAWL).

Regulation and mechanism

YKL-40 has been linked to activation of the AKT pro-survival (anti-apoptotic) signaling pathway. YKL-40 promotes angiogenesis through VEGF-dependent and independent pathways.^[6]

YKL-40 is a migration factor for primary astrocytes and its expression is controlled by NFI-X3, STAT3, and AP-1.^[7]

CHI3l1 is induced by a variety of cancers and in the presence of semaphorin 7A (protein) can inhibit multiple anti-tumor immune system responses. Activating an antiviral immune pathway known as the RIG-like helicase (RLH) has the ability to counter CHI3l1 induction. Cancer cells can offset RLH by stimulating NLRX1. Poly(I:C), an RNA-like molecule, can stimulate RLH activation. RLH activation can also inhibit the expression of receptor IL-13Rα2 and pulmonary metastasis. It stores NK cell accumulation and activation. It augments the expression of IFN-α/β, chemerin and its receptor ChemR23, p-cofilin, LIMK2 and PTEN and inhibiting BRAF and NLRX1 in a MAVS-dependent manner.^[8]

Cancer

It is assumed that YKL-40 plays a role in cancer cell proliferation, survival, invasiveness and in the regulation of cell-matrix interactions. It is suggested that YKL-40 is a marker associated with a poorer clinical outcome in genetically defined subgroups of different tumors. YKL-40 was recently introduced into (restricted) clinical practice. A few techniques are available for its detection.

YKL-40 is a Th2 promoting cytokine that is present at high levels in the tumor microenvironment and in the serum of cancer patients.^{[9] [10]} Elevated levels of YKL-40 correlate strongly with stage and outcome of various types of cancer, which establish YKL-40 as a biomarker of disease severity.^[11] Targeting YKL-40 with neutralizing antibodies is effective as a treatment in animal models of glioblastoma multiforme.^[12]

YKL-40 also enhances tumor survival in response to gamma-irradiation.^[6]

Alzheimer's disease and neurodegeneration

As Alzheimer's disease progresses, soluble amyloid beta aggregates in the brain can induce the activation of microglia, which triggers synthesis of pro-inflammatory mediators.^[13] This leads to increased Chi3l1 expression in astrocytes. There is evidence that YKL-40 levels are elevated in Alzheimer's patients compared to cognitively normal individuals. Elevated levels of YKL-40 mRNA were found in Alzheimer's-inflicted brains in comparison with normal controls. Additionally, YKL-40 is correlated other dementia biomarkers, such as tau proteins and amyloid beta. YKL-40 is being examined as a novel Alzheimer's biomarker quantified in the cerebrospinal fluid or blood.^[14]

In Huntington's disease YKL-40 has an increasing trend in cerebrospinal fluid in the later disease stages and correlates highly with symptom severity.^{[15] [16]}

References

Further reading

• Rathcke CN, Vestergaard H . YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis . Inflammation Research . 55 . 6 . 221–7 . June 2006 . 16955240 . 10.1007/s00011-006-0076-y . 25462930 .
• Nyirkos P, Golds EE . Human synovial cells secrete a 39 kDa protein similar to a bovine mammary protein expressed during the non-lactating period . The Biochemical Journal . 269 . 1 . 265–8 . July 1990 . 2375755 . 1131563 . 10.1042/bj2690265 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Kirkpatrick RB, Emery JG, Connor JR, Dodds R, Lysko PG, Rosenberg M . Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages . Experimental Cell Research . 237 . 1 . 46–54 . November 1997 . 9417865 . 10.1006/excr.1997.3764 .
• Renkema GH, Boot RG, Au FL, Donker-Koopman WE, Strijland A, Muijsers AO, Hrebicek M, Aerts JM . Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages . European Journal of Biochemistry . 251 . 1–2 . 504–9 . January 1998 . 9492324 . 10.1046/j.1432-1327.1998.2510504.x . free .
• Johansen JS, Stoltenberg M, Hansen M, Florescu A, Hørslev-Petersen K, Lorenzen I, Price PA . Serum YKL-40 concentrations in patients with rheumatoid arthritis: relation to disease activity . Rheumatology . 38 . 7 . 618–26 . July 1999 . 10461474 . 10.1093/rheumatology/38.7.618 . free .
• Nordenbaek C, Johansen JS, Junker P, Borregaard N, Sørensen O, Price PA . YKL-40, a matrix protein of specific granules in neutrophils, is elevated in serum of patients with community-acquired pneumonia requiring hospitalization . The Journal of Infectious Diseases . 180 . 5 . 1722–6 . November 1999 . 10515841 . 10.1086/315050 . free .
• Connor JR, Dodds RA, Emery JG, Kirkpatrick RB, Rosenberg M, Gowen M . Human cartilage glycoprotein 39 (HC gp-39) mRNA expression in adult and fetal chondrocytes, osteoblasts and osteocytes by in-situ hybridization . Osteoarthritis and Cartilage . 8 . 2 . 87–95 . March 2000 . 10772238 . 10.1053/joca.1999.0276 . free .
• Østergaard C, Johansen JS, Benfield T, Price PA, Lundgren JD . YKL-40 is elevated in cerebrospinal fluid from patients with purulent meningitis . Clinical and Diagnostic Laboratory Immunology . 9 . 3 . 598–604 . May 2002 . 11986266 . 119997 . 10.1128/CDLI.9.3.598-604.2002 .
• Kronborg G, Ostergaard C, Weis N, Nielsen H, Obel N, Pedersen SS, Price PA, Johansen JS . Serum level of YKL-40 is elevated in patients with Streptococcus pneumoniae bacteremia and is associated with the outcome of the disease . Scandinavian Journal of Infectious Diseases . 34 . 5 . 323–6 . 2003 . 12069012 . 10.1080/00365540110080233 . 24431773 .
• Recklies AD, White C, Ling H . The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways . The Biochemical Journal . 365 . Pt 1 . 119–26 . July 2002 . 12071845 . 1222662 . 10.1042/BJ20020075 .
• Cintin C, Johansen JS, Christensen IJ, Price PA, Sørensen S, Nielsen HJ . High serum YKL-40 level after surgery for colorectal carcinoma is related to short survival . Cancer . 95 . 2 . 267–74 . July 2002 . 12124825 . 10.1002/cncr.10644 . free .
• Steck E, Breit S, Breusch SJ, Axt M, Richter W . Enhanced expression of the human chitinase 3-like 2 gene (YKL-39) but not chitinase 3-like 1 gene (YKL-40) in osteoarthritic cartilage . Biochemical and Biophysical Research Communications . 299 . 1 . 109–15 . November 2002 . 12435396 . 10.1016/S0006-291X(02)02585-8 .
• Steenbakkers PG, Baeten D, Rovers E, Veys EM, Rijnders AW, Meijerink J, De Keyser F, Boots AM . Localization of MHC class II/human cartilage glycoprotein-39 complexes in synovia of rheumatoid arthritis patients using complex-specific monoclonal antibodies . Journal of Immunology . 170 . 11 . 5719–27 . June 2003 . 12759455 . 10.4049/jimmunol.170.11.5719 . free .
• Houston DR, Recklies AD, Krupa JC, van Aalten DM . Structure and ligand-induced conformational change of the 39-kDa glycoprotein from human articular chondrocytes . The Journal of Biological Chemistry . 278 . 32 . 30206–12 . August 2003 . 12775711 . 10.1074/jbc.M303371200 . free .
• Nishikawa KC, Millis AJ . gp38k (CHI3L1) is a novel adhesion and migration factor for vascular cells . Experimental Cell Research . 287 . 1 . 79–87 . July 2003 . 12799184 . 10.1016/S0014-4827(03)00069-7 .

Notes and References

1. Hakala BE, White C, Recklies AD . Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family . The Journal of Biological Chemistry . 268 . 34 . 25803–10 . December 1993 . 10.1016/S0021-9258(19)74461-5 . 8245017 . free .
2. Rehli M, Krause SW, Andreesen R . Molecular characterization of the gene for human cartilage gp-39 (CHI3L1), a member of the chitinase protein family and marker for late stages of macrophage differentiation . Genomics . 43 . 2 . 221–5 . July 1997 . 9244440 . 10.1006/geno.1997.4778 .
3. Web site: Entrez Gene: CHI3L1 chitinase 3-like 1 (cartilage glycoprotein-39).
4. Kazakova MH, Sarafian VS . YKL-40--a novel biomarker in clinical practice? . Folia Medica . 51 . 1 . 5–14 . 2009-03-01 . 19437893 .
5. Ober C, Tan Z, Sun Y, Possick JD, Pan L, Nicolae R, Radford S, Parry RR, Heinzmann A, Deichmann KA, Lester LA, Gern JE, Lemanske RF, Nicolae DL, Elias JA, Chupp GL . Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function . The New England Journal of Medicine . 358 . 16 . 1682–91 . April 2008 . 18403759 . 2629486 . 10.1056/NEJMoa0708801 .
6. Francescone RA, Scully S, Faibish M, Taylor SL, Oh D, Moral L, Yan W, Bentley B, Shao R . Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma . The Journal of Biological Chemistry . 286 . 17 . 15332–43 . April 2011 . 21385870 . 3083166 . 10.1074/jbc.M110.212514 . free .
7. Singh SK, Bhardwaj R, Wilczynska KM, Dumur CI, Kordula T . A complex of nuclear factor I-X3 and STAT3 regulates astrocyte and glioma migration through the secreted glycoprotein YKL-40 . The Journal of Biological Chemistry . 286 . 46 . 39893–903 . November 2011 . 21953450 . 3220556 . 10.1074/jbc.M111.257451 . free .
8. Ma B, Herzog EL, Moore M, Lee CM, Na SH, Lee CG, Elias JA . RIG-like Helicase Regulation of Chitinase 3-like 1 Axis and Pulmonary Metastasis . Scientific Reports . 6 . 26299 . May 2016 . 27198666 . 4873814 . 10.1038/srep26299 . 2016NatSR...626299M .
9. Høgdall EV, Ringsholt M, Høgdall CK, Christensen IJ, Johansen JS, Kjaer SK, Blaakaer J, Ostenfeld-Møller L, Price PA, Christensen LH . YKL-40 tissue expression and plasma levels in patients with ovarian cancer . BMC Cancer . 9 . 8 . January 2009 . 19134206 . 2645422 . 10.1186/1471-2407-9-8 . free .
10. Bernardi D, Padoan A, Ballin A, Sartori M, Manara R, Scienza R, Plebani M, Della Puppa A . Serum YKL-40 following resection for cerebral glioblastoma . Journal of Neuro-Oncology . 107 . 2 . 299–305 . April 2012 . 22102082 . 10.1007/s11060-011-0762-7 . 36048348 .
11. Johansen JS, Christensen IJ, Riisbro R, Greenall M, Han C, Price PA, Smith K, Brünner N, Harris AL . High serum YKL-40 levels in patients with primary breast cancer is related to short recurrence free survival . Breast Cancer Research and Treatment . 80 . 1 . 15–21 . July 2003 . 12889595 . 10.1023/A:1024431000710 . 29295642 .
12. Faibish M, Francescone R, Bentley B, Yan W, Shao R . A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers . Molecular Cancer Therapeutics . 10 . 5 . 742–51 . May 2011 . 21357475 . 3091949 . 10.1158/1535-7163.MCT-10-0868 .
13. Muszyński P, Groblewska M, Kulczyńska-Przybik A, Kułakowska A, Mroczko B . YKL-40 as a Potential Biomarker and a Possible Target in Therapeutic Strategies of Alzheimer's Disease . Current Neuropharmacology . 15 . 6 . 906–917 . 2017-07-31 . 28183245 . 10.2174/1570159X15666170208124324 . 5652033 .
14. Molinuevo JL, Ayton S, Batrla R, Bednar MM, Bittner T, Cummings J, Fagan AM, Hampel H, Mielke MM, Mikulskis A, O'Bryant S, Scheltens P, Sevigny J, Shaw LM, Soares HD, Tong G, Trojanowski JQ, Zetterberg H, Blennow K . Current state of Alzheimer's fluid biomarkers . Acta Neuropathologica . 136 . 6 . 821–853 . December 2018 . 30488277 . 6280827 . 10.1007/s00401-018-1932-x .
15. Vinther-Jensen. Tua. Budtz-Jørgensen. Esben. Simonsen. Anja H.. Nielsen. Jørgen E.. Hjermind. Lena E.. November 2014. YKL-40 in cerebrospinal fluid in Huntington's disease--a role in pathology or a nonspecific response to inflammation?. Parkinsonism & Related Disorders. 20. 11. 1301–1303. 10.1016/j.parkreldis.2014.08.011. 1873-5126. 25219973.
16. Niemelä. Valter. Burman. Joachim. Blennow. Kaj. Zetterberg. Henrik. Larsson. Anders. Sundblom. Jimmy. 2018. Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease. PLOS ONE. 13. 2. e0193492. 10.1371/journal.pone.0193492. 1932-6203. 5825143. 29474427. 2018PLoSO..1393492N. free.