CHI3L1

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. 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.

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

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.

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. 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. Targeting YKL-40 with neutralizing antibodies is effective as a treatment in animal models of glioblastoma multiforme.

YKL-40 also enhances tumor survival in response to gamma-irradiation.

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. 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.

In Huntington's disease YKL-40 has an increasing trend in cerebrospinal fluid in the later disease stages and correlates highly with symptom severity.

References

References

1. (December 1993). "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.
2. (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.
3. "Entrez Gene: CHI3L1 chitinase 3-like 1 (cartilage glycoprotein-39)".
4. (2009-03-01). "YKL-40--a novel biomarker in clinical practice?". Folia Medica.
5. (April 2008). "Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function". The New England Journal of Medicine.
6. (April 2011). "Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma". The Journal of Biological Chemistry.
7. (November 2011). "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.
8. (May 2016). "RIG-like Helicase Regulation of Chitinase 3-like 1 Axis and Pulmonary Metastasis". Scientific Reports.
9. (January 2009). "YKL-40 tissue expression and plasma levels in patients with ovarian cancer". BMC Cancer.
10. (April 2012). "Serum YKL-40 following resection for cerebral glioblastoma". Journal of Neuro-Oncology.
11. (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.
12. (May 2011). "A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers". Molecular Cancer Therapeutics.
13. (2017-07-31). "YKL-40 as a Potential Biomarker and a Possible Target in Therapeutic Strategies of Alzheimer's Disease". Current Neuropharmacology.
14. (December 2018). "Current state of Alzheimer's fluid biomarkers". Acta Neuropathologica.
15. (November 2014). "YKL-40 in cerebrospinal fluid in Huntington's disease--a role in pathology or a nonspecific response to inflammation?". Parkinsonism & Related Disorders.
16. (2018). "Cerebrospinal fluid sCD27 levels indicate active T cell-mediated inflammation in premanifest Huntington's disease". PLOS ONE.