Chitinase-3-like protein 1 (CHI3L1), also known as YKL-40, is a secretedglycoprotein that is approximately 40kDa in size that in humans is encoded by the CHI3L1gene.[5][6][7] 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[8] and asthma.[9]
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.[7] YKL-40 lacks chitinase activity due to mutations within the active site (conserved sequence: DXXDXDXE; YKL-40 sequence: DGLDLAWL).[8]
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.[10]
YKL-40 is a migration factor for primary astrocytes and its expression is controlled by NFI-X3, STAT3, and AP-1.[11]
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.[12]
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.[8]
YKL-40 is a Th2 promoting cytokine that is present at high levels in the tumor microenvironment and in the serum of cancer patients.[13][14] 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.[15] Targeting YKL-40 with neutralizing antibodies is effective as a treatment in animal models of glioblastoma multiforme.[16]
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.[17] This leads to increased Chi3l1 expression in astrocytes.[17] There is evidence that YKL-40 levels are elevated in Alzheimer's patients compared to cognitively normal individuals.[17] Elevated levels of YKL-40 mRNA were found in Alzheimer's-inflicted brains in comparison with normal controls.[17] Additionally, YKL-40 is correlated other dementia biomarkers, such as tau proteins and amyloid beta.[17] YKL-40 is being examined as a novel Alzheimer's biomarker quantified in the cerebrospinal fluid or blood.[18]
In Huntington's disease YKL-40 has an increasing trend in cerebrospinal fluid in the later disease stages and correlates highly with symptom severity.[19][20]
^Rehli M, Krause SW, Andreesen R (July 1997). "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. doi:10.1006/geno.1997.4778. PMID9244440.
^Bernardi D, Padoan A, Ballin A, Sartori M, Manara R, Scienza R, Plebani M, Della Puppa A (April 2012). "Serum YKL-40 following resection for cerebral glioblastoma". Journal of Neuro-Oncology. 107 (2): 299–305. doi:10.1007/s11060-011-0762-7. PMID22102082. S2CID36048348.
^Johansen JS, Christensen IJ, Riisbro R, Greenall M, Han C, Price PA, Smith K, Brünner N, Harris AL (July 2003). "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. doi:10.1023/A:1024431000710. PMID12889595. S2CID29295642.
Rathcke CN, Vestergaard H (June 2006). "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. doi:10.1007/s00011-006-0076-y. PMID16955240. S2CID25462930.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Kirkpatrick RB, Emery JG, Connor JR, Dodds R, Lysko PG, Rosenberg M (November 1997). "Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages". Experimental Cell Research. 237 (1): 46–54. doi:10.1006/excr.1997.3764. PMID9417865.
Kronborg G, Ostergaard C, Weis N, Nielsen H, Obel N, Pedersen SS, Price PA, Johansen JS (2003). "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. doi:10.1080/00365540110080233. PMID12069012. S2CID24431773.
Steck E, Breit S, Breusch SJ, Axt M, Richter W (November 2002). "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. doi:10.1016/S0006-291X(02)02585-8. PMID12435396.
