Significance of chitinase-3-like protein 1 in the pathogenesis of inflammatory diseases and cancer.

The most studied mammalian chitinases are chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase), which are both true chitinases, whereas CHI3L1, chitinase-3-like 2 (CHI3L2), oviductal glycoprotein 1 (OVGP1), and stabilin-1 interacting chitinase like protein (S1-CLP) have the ability to bind chitin but not to degrade it. The properties of CLPs, including CHI3L1, are summarized in Table 1 . Table 1 Properties of CLP isoforms. CHI3L1 CHI3L2 OVGP1 S1-CLP Biological activities Carbohydrate and chitin binding Carbohydrate and chitin binding Saccharides and oligosaccharides binding Oligosaccharide, chitin and protein binding Expressing cells Neutrophils, synoviocytes, monocytes/macrophages, osteoclasts, endothelial cell, hepatic stellate cells, smooth muscle cells, and many cancer cells Synovial fibroblasts, human cartilage chondrocytes, and cancer cells Oviductal epithelial cell Macrophages, monocytes, lymphocytes, and sinusoidal endothelial cells, cancer cells Possible functions Regulation of cell proliferation, adhesion, migration, and activation Activation of macrophages Regulation of immune-response in inflammation and cancer Cartilage biogenesis Type II collagen expression Regulation of immune-response Supportive role in fertilization and embryo development A ligand for the multifunctional receptor stabilin-1, macrophage inflammatory regulator, pathogen sensing, endotoxin neutralization Associated diseases Pneumonia, rheumatoid arthritis, breast cancer, colon cancer, ovarian carcinoma, hepatocellular carcinoma, lung cancer, atherosclerosis, atopy, liver fibrosis, depression, schizophrenia, and Alzheimer’s disease, Parkinson disease, obesity, diabetes, asthma etc. Rheumatoid arthritis, Osteoarthritis, Alzheimer’s disease, renal, glioma and breast cancer Ovarian cancers, mucinous carcinomas’ hypertension, endometriosis Rheumatoid arthritis, osteoarthritis chronic obstructive pulmonary disease, sarcoidosis Properties of CLP isoforms. Regulation of cell proliferation, adhesion, migration, and activation Activation of macrophages Regulation of immune-response in inflammation and cancer Cartilage biogenesis Type II collagen expression Regulation of immune-response Among them, CHI3L1 has been called YKL-40 in humans and breast regression protein 39 (BRP-39) in mice 10 . CHI3L1 is derived from the three N-terminal amino acids present on the secreted form and its molecular mass. Since its initial detection in the culture supernatant of the MG63 osteosarcoma cell line, it has been subsequently discovered in human chondrocytes, synoviocytes, and vascular smooth muscle cells 11 – 13 . CHI3L1 protein shows high conservation among species, with homologies of 73.3% in mice, 79.6% in rats, 96.6% in monkeys, and 83.8% in sheep. CHI3L1 is a 40-kDa glycoprotein with heparin, chitin, and collagen-binding properties. It acts as a lectin due to its preserved carbohydrate-binding domain, but its ligands are still unknown 14 – 17 . CHI3L1 is strongly expressed by macrophages in inflammatory diseases, such as rheumatoid arthritis, asthma, liver cirrhosis, encephalitis, stroke, multiple sclerosis, and glioblastoma 18 – 27 . It is noteworthy that CHI3L1 has the ability to bind to multiple receptors, such as the receptor for advanced glycation end products (RAGE), syndecan-1/αVβ3, interleukin 13 receptor alpha 2 (IL-13Rα2), and VEGFR2, and this binding leads to the activation of several signals related to inflammasome activation, neuronal inflammation, tumor metastasis and invasion, angiogenesis, apoptosis, carcinogenesis, Aβ accumulation, vascular smooth muscle cell activation, endothelial cell inflammation and atherogenesis (Fig. 2 ) 28 – 30 . Fig. 2 The role of CHI3L1 in signaling pathways for the development of various diseases. Various cells, such as monocytes, neutrophils, macrophages, epithelial cells, Kupffer cells, osteoclasts, chondrocytes, smooth muscle cells, astrocytes, and cancer cells, produce CHI3L1 by the stimulation of several interleukins, such as IL-13, IL-6, IL-1β, and TNF-α. CHI3L1 expression is inhibited by miR-24, miR-342-3p, miR-449, miR125p-39, and miR-96-5p. The activated cells can release (or produce) IL-1β, TNF-α, IL-6, IL-8, IL-10, IL-12, NO, CXCL9, and CXCL11. In the development of atherogenesis, CHI3L1 directly induces PDGF and PDGFR expression to activate VSMCs and/or directly induces VCAM1 and eNOS expression in the cytosol to cause EC inflammation. In the development of neurodegenerative diseases, CHI3L1 activates the MAPK and NF-кB signaling pathways to induce Aβ accumulation and neuronal inflammation via RAGE in either astrocytes or neurons. In neuronal cells, CHI3L1 activity leads to increased expression of CD14 and TLR4 through the MAPK and NF-кB signaling pathways to damage neurons. In cancer development, several receptors and signaling pathways are involved in these processes. CHI3l1 binds to its receptor IL-13Rα2 by associating with TMEM219 directly or by physically interacting with CD44. The TMEM219-dependent pathway prevents cell death by activating the ERK1/2 and AKT pathways, but direct interaction with IL-13Rα2 causes apoptosis through activation of Wnt/β-catenin. Physical interaction with CD44 activates the AKT pathway to induce metastasis and invasion. The membrane receptors syndecan-1 and integrin α v β 5 trigger CHI3L1 signaling pathways, causing tumor vascular permeability and growth by activating the β-catenin, FAK, and ERK 1/2 (MAPK) pathways. CHI3L1 also binds to RAGE and thus activates the FAK and STAT3 pathways, inducing tumor growth. In addition, CHI3L1 elevates the expression of VEGF and its receptor to cause angiogenesis via the activation of the JNK and p38 signaling pathways. Various cells, such as monocytes, neutrophils, macrophages, epithelial cells, Kupffer cells, osteoclasts, chondrocytes, smooth muscle cells, astrocytes, and cancer cells, produce CHI3L1 by the stimulation of several interleukins, such as IL-13, IL-6, IL-1β, and TNF-α. CHI3L1 expression is inhibited by miR-24, miR-342-3p, miR-449, miR125p-39, and miR-96-5p. The activated cells can release (or produce) IL-1β, TNF-α, IL-6, IL-8, IL-10, IL-12, NO, CXCL9, and CXCL11. In the development of atherogenesis, CHI3L1 directly induces PDGF and PDGFR expression to activate VSMCs and/or directly induces VCAM1 and eNOS expression in the cytosol to cause EC inflammation. In the development of neurodegenerative diseases, CHI3L1 activates the MAPK and NF-кB signaling pathways to induce Aβ accumulation and neuronal inflammation via RAGE in either astrocytes or neurons. In neuronal cells, CHI3L1 activity leads to increased expression of CD14 and TLR4 through the MAPK and NF-кB signaling pathways to damage neurons. In cancer development, several receptors and signaling pathways are involved in these processes. CHI3l1 binds to its receptor IL-13Rα2 by associating with TMEM219 directly or by physically interacting with CD44. The TMEM219-dependent pathway prevents cell death by activating the ERK1/2 and AKT pathways, but direct interaction with IL-13Rα2 causes apoptosis through activation of Wnt/β-catenin. Physical interaction with CD44 activates the AKT pathway to induce metastasis and invasion. The membrane receptors syndecan-1 and integrin α v β 5 trigger CHI3L1 signaling pathways, causing tumor vascular permeability and growth by activating the β-catenin, FAK, and ERK 1/2 (MAPK) pathways. CHI3L1 also binds to RAGE and thus activates the FAK and STAT3 pathways, inducing tumor growth. In addition, CHI3L1 elevates the expression of VEGF and its receptor to cause angiogenesis via the activation of the JNK and p38 signaling pathways.

The development of other inflammatory diseases, such as rheumatoid arthritis (RA) and atopy, also involves the expression of CHI3L1. RA is an autoimmune disease that induces chronic inflammation of the joints. Several studies have suggested that CHI3L1 is a candidate autoantigen for inducing an autoimmune response in RA 184 – 189 . For example, patients with RA exhibited high levels of circulating CHI3L1, with high concentrations in synovial cells 190 , 191 . Moreover, cells that positively stained for major histocompatibility complex/human cartilage CHI3L1 complexes were observed in 61.5% of inflamed RA synovial samples compared with only 3.0% of the control samples in a specific and independent manner; therefore, CHI3L1 may be useful as a histological marker for the immunopathological diagnosis of RA 192 . Articular chondrocytes, synovial cells, infiltrated macrophages, and neutrophils can produce CHI3L1 in RA-affected joints. In RA, levels of proinflammatory mediators (MMP-3, IL-6, IFN-γ, and TNF-α) correlate with CHI3L1, and anti-rheumatic factor therapy reduces CHI3L1 levels in patients 193 – 196 . The treatment of cartilage explants from young bovine stifle joints with IL-1β and TNF-α increased the release of CHI3L1 in association with an innate immune and stress response by chondrocytes, which may play a role in the host defense against pathogens or may protect cells against stress-induced damage 197 . In addition, miR-24 reduced the osteoblast apoptosis, abnormal bone formation, and mineralization induced by Staphylococcus aureus by inhibiting the expression of CHI3L1 198 . In turn, CHI3L1 was detected in RA synovial fluid and tissue from patients with arthritis, and the synovial fluid of three out of 10 patients with spondylarthritis exhibited endogenous CHI3L1 expression 186 . In a serum analysis of 25 patients with RA, we found that CHI3L1 levels in patients with RA were significantly higher than the normal level, and the elevated levels did not deviate among the patients. We also found that the receiver operating characteristic curve of CHI3L1 yielded an AUC value of 0.955, which is slightly lower than the AUC values of the US FDA-recommended RA diagnostic factors, i.e., CRP (0.988) and cyclic citrullinated peptide (CCP, 0.995), but slightly higher than that of rheumatoid factor (0.865). There are a few reports of CHI3L1 as a target for the treatment of atopy. In fact, the serum levels of CHI3L1 were found to be significantly increased in patients with atopy compared with healthy controls 199 . A recent study indicated that CHI3L1 KO reduced allergic skin inflammation through the inhibition of Th2-mediated inflammation and M2 macrophage activation 102 . Moreover, the g.-247C/T polymorphism located in the CHI3L1 promoter region is associated with the risk of atopy in Korean children 200 . Previously, we found that suppressing CHI3L1 alleviated atopic dermatitis-like skin inflammation by inhibiting NF-κB-mediated ITGA5 expression in CHI3L1 knockout mice 201 . In addition, treatment with a CHI3L1 siRNA reduced the levels of these inflammatory cytokines in TNF-α/IFN-γ-treated cells. Additionally, the administration of a commercially available anti-CHI3L1 antibody significantly alleviated atopic symptoms, reducing atopy-related cytokines and inflammatory cell recruitment. The AUC value for CHI3L1 (0.932) was significantly higher than that for IL-4 (0.650), IL-13 (0.785), and IL-1β (0.790) in the serum analysis of 20 atopy patients. DUPIXENT@ is the first FDA-approved biologic therapy targeting IL-4Rα, thereby inhibiting IL-4 and IL-13 signaling and reducing type 2 inflammation. Finally, we found that the CHI3L1-inhibiting Compound K284-6111 completely reduced atopy skin inflammation 202 . These findings suggest that CHI3L1 plays a role in the development of RA and atopy and is a good candidate therapeutic target for these inflammatory diseases.

Although several studies on chitinase-3-like 1 (CHI3L1) have been published, a systematic review of the various features and functions of this protein is lacking. In this review article, we provide information based on an analysis of the available data using an Open Targets Platform 1 – 3 and other data-analysis platforms to assess the significance of CHI3L1 as a target molecule in several inflammatory diseases. We also provide further information regarding the interacting target of CHI3L1 obtained using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which is a comprehensive web-based platform that lists known and predicted protein–protein interactions 4 – 9 . Furthermore, we discuss recent findings related to the roles of CHI3L1 in the development of several inflammatory diseases, as well as in therapeutic approaches. Using the Open Targets Platform, we found that several cancers, neurological diseases, pulmonary diseases, cardiovascular diseases, and rheumatoid arthritis, among others, are critically associated with CHI3L1 (Fig. 1 ). Thus, here, we discuss the significant roles of CHI3L1 in the development of cancers (lung, liver, and colon), neurological diseases (Alzheimer’s disease, schizophrenia, etc.), cardiovascular diseases, and rheumatoid arthritis; moreover, we provide some information pertaining to the significance of CHI3L1 in the most common autoimmune disease among Korean children, i.e., atopy. Fig. 1 Relationship between CHI3L1 and various diseases. The circle sizes are determined based on text-mining scores. The values in the circle symbols are the text-mining scores determined via Open Targets Platform analysis. The circle sizes are determined based on text-mining scores. The values in the circle symbols are the text-mining scores determined via Open Targets Platform analysis.