The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer.

In triple-negative breast cancer (TNBC), stromal restriction of CD8+ T cells associates with poor clinical outcomes and lack of responsiveness to immune-checkpoint blockade (ICB). To identify mediators of T cell stromal restriction, we profiled murine breast tumors lacking the transcription factor Stat3, which is commonly hyperactive in breast cancers and promotes an immunosuppressive tumor microenvironment. Expression of the cytokine Chi3l1 was decreased in Stat3-/- tumors. CHI3L1 expression was elevated in human TNBCs and other solid tumors exhibiting T cell stromal restriction. Chi3l1 ablation in the polyoma virus middle T (PyMT) breast cancer model generated an anti-tumor immune response and delayed mammary tumor onset. These effects were associated with increased T cell tumor infiltration and improved response to ICB. Mechanistically, Chi3l1 promoted neutrophil recruitment and neutrophil extracellular trap formation, which blocked T cell infiltration. Our findings provide insight into the mechanism underlying stromal restriction of CD8+ T cells and suggest that targeting Chi3l1 may promote anti-tumor immunity in various tumor types.

SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1.

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.

Chitinase-3 like-protein-1, a prognostic biomarker in patients with hepatocellular carcinoma and concomitant myosteatosis.

BACKGROUND: Chitinase-3 like-protein-1 (CHI3L1) is a member of the mammalian chitinase-like proteins and elevated serum CHI3L1 level has been proved to be associated with poor prognosis in hepatocellular carcinoma (HCC). This study aimed to investigate the relationship between serum CHI3L1 levels and body composition parameters in patients with HCC after liver transplantation (LT). METHODS: This retrospective study enrolled 200 patients after LT for HCC. Blood samples were collected and serum concentrations of CHI3L1 were measured by enzyme-linked immunosorbent assay. Computer tomography (CT) were used to estimate skeletal muscle and adipose tissue mass. Spearman's rank correlation test was performed to assess associations between serum CHI3L1 levels and these body composition parameters. A Cox proportional-hazards regression model was performed to identify independent prognostic factors. Overall survival (OS) and recurrence-free survival (RFS) curves were constructed using the Kaplan-Meier method and compared by the log-rank test. RESULTS: Total 71 patients (35.5%) were diagnosed with myosteatosis according to skeletal muscle radiation attenuation (SMRA). The 5-year OS rates were 66.9% in non-myosteatosis group, significantly higher than 49.5% in myosteatosis group (p = 0.025), while the RFS of myosteatosis group (5-year RFS: 52.6%) or non-myosteatosis group (5-year RFS: 42.0%) shown no significant difference (p = 0.068). The serum CHI3L1 level were significantly negative correlated with SMRA (r = -0.3, p < 0.001). Interestingly, in patients with myosteatosis, Kaplan-Meier analysis revealed that elevated serum CHI3L1 levels were associated with worse OS (p < 0.001) and RFS (p = 0.047). However, in patients without myosteatosis, Kaplan-Meier analysis found elevated serum CHI3L1 levels were not associated with OS (p = 0.070) or RFS (p = 0.104). CONCLUSIONS: Elevated CHI3L1 was negatively correlated with SMRA, and predicted poorer prognosis in Chinese population after LT for HCC, especially in those patients with concomitant myosteatosis. Monitoring serum CHI3L1 can predict prognosis and effectively guide individual nutrition intervention.

IL13Rα2 as a crucial receptor for Chi3l1 in osteoclast differentiation and bone resorption through the MAPK/AKT pathway.

BACKGROUND: Previous research has revealed that the 18 glycoside hydrolase gene family (GH18) member Chitinase 3-like 1 (Chi3l1) can regulate osteoclast differentiation and bone resorption. However, its downstream receptors and molecular mechanisms during osteoclastogenesis have yet to be elucidated. METHODS: Initially, we conducted a comprehensive investigation to evaluate the effects of recombinant Chi3l1 protein or Chi3l1 siRNA on osteoclast differentiation and the RANKL-induced MAPK/AKT signaling pathways. Moreover, we used immunofluorescence and immunoprecipitation assays to identify IL13Rα2 as the downstream receptor of Chi3l1. Subsequently, we investigated the impact of IL13Rα2 recombinant protein or IL13Rα2-siRNA on osteoclast differentiation and the associated signaling pathways. Finally, we performed in vivo experiments to examine the effect of recombinant IL13Rα2 protein in an LPS-induced mouse model of cranial osteolysis. RESULTS: Our findings highlight that the administration of recombinant Chi3l1 protein increased the formation of osteoclasts and bolstered the expression of several osteoclast-specific genes (TRAP, NFATC1, CTR, CTSK, V-ATPase d2, and Dc-STAMP). Additionally, Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK) and AKT pathway activation, whereas Chi3l1 silencing inhibited this process. Next, using immunofluorescence and co-immunoprecipitation assays, we identified IL13Rα2 as the binding partner of Chi3l1 during osteoclastogenesis. IL13Rα2 recombinant protein or IL13Rα2-siRNA also inhibited osteoclast differentiation, and IL13Rα2-siRNA attenuated the RANKL-induced activation of the MAPK (ERK/P38/JNK) and AKT pathways, similar to the effects observed upon silencing of Chi3l1. Moreover, the promoting effect of recombinant Chi3l1 protein on osteoclastogenesis and the activation of the MAPK and AKT pathways was reversed by IL13Rα2 siRNA. Finally, recombinant LI13Rα2 protein significantly attenuated the LPS-induced cranial osteolysis and the number of osteoclasts in vivo. CONCLUSIONS: Our findings suggested that IL13Rα2 served as a crucial receptor for Chi3l1, enhancing RANKL-induced MAPK and AKT activation to promote osteoclast differentiation. These findings provide valuable insights into the molecular mechanisms of Chi3l1 in osteoclastogenesis, with potential therapeutic implications for osteoclast-related diseases. Video Abstract.

Chitinases as a potential diagnostic and prognostic biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons, and there is currently a lack of reliable diagnostic biomarkers. This meta-analysis aimed to evaluate CHIT1, CHI3L1, and CHI3L2 levels in the cerebrospinal fluid (CSF) or blood and their diagnostic potential in ALS patients. A systematic, comprehensive search was performed of peer-reviewed English-language articles published before April 1, 2023, in PubMed, Scopus, Embase, Cochrane Library, and Web of Science. After a thorough screening, 13 primary articles were included, and their chitinases-related data were extracted for systematic review and meta-analysis. In ALS patients, the CSF CHIT1 levels were significantly elevated compared to controls with healthy control (HC) (SMD, 1.92; 95% CI, 0.78 - 3.06; P < 0.001). CHIT1 levels were elevated in the CSF of ALS patients compared to other neurodegenerative diseases (ONDS) control (SMD, 0.74; 95% CI, 0.22 - 1.27; P < 0.001) and exhibited an even more substantial increase when compared to ALS-mimicking diseases (AMDS) (SMD, 1.15; 95% CI, 0.35 - 1.94, P < 0.001). Similarly, the CSF CHI3L1 levels were significantly higher in ALS patients compared to HC (SMD, 3.16; 95% CI, 1.26 - 5.06, P < 0.001). CHI3L1 levels were elevated in the CSF of ALS patients compared to ONDS (SMD, 0.75; 95% CI, 0.32 - 1.19; P = 0.017) and exhibited a more pronounced increase when compared to AMDS (SMD, 1.92; 95% CI, 0.41 - 3.42; P < 0.001). The levels of CSF chitinases in the ALS patients showed a significant increase, supporting the role of CSF chitinases as diagnostic biomarkers for ALS.

Chitinase 3-like 1 is a profibrogenic factor overexpressed in the aging liver and in patients with liver cirrhosis.

Older age at the time of infection with hepatitis viruses is associated with an increased risk of liver fibrosis progression. We hypothesized that the pace of fibrosis progression may reflect changes in gene expression within the aging liver. We compared gene expression in liver specimens from 54 adult donors without evidence of fibrosis, including 36 over 40 y old and 18 between 18 and 40 y old. Chitinase 3-like 1 (CHI3L1), which encodes chitinase-like protein YKL-40/CHI3L1, was identified as the gene with the greatest age-dependent increase in expression in liver tissue. We investigated the cellular source of CHI3L1 in the liver and its function using liver tissue specimens and in vitro models. CHI3L1 expression was significantly higher in livers of patients with cirrhosis of diverse etiologies compared with controls represented by patients who underwent liver resection for hemangioma. The highest intrahepatic CHI3L1 expression was observed in cirrhosis due to hepatitis D virus, followed by hepatitis C virus, hepatitis B virus, and alcohol-induced cirrhosis. In situ hybridization of CHI3L1 messenger RNA (mRNA) identified hepatocytes as the major producers of CHI3L1 in normal liver and in cirrhotic tissue, wherein hepatocytes adjacent to fibrous septa showed higher CHI3L1 expression than did those in more distal areas. In vitro studies showed that recombinant CHI3L1 promotes proliferation and activation of primary human hepatic stellate cells (HSCs), the major drivers of liver fibrosis. These findings collectively demonstrate that CHI3L1 promotes liver fibrogenesis through a direct effect on HSCs and support a role for CHI3L1 in the increased susceptibility of aging livers to fibrosis progression.

EGR1 mediates METTL3/m6A/CHI3L1 to promote osteoclastogenesis in osteoporosis.

OBJECTIVE: To investigate EGR1-mediated METTL3/m6A/CHI3L1 axis in osteoporosis. METHODS: Ovariectomy (OVX) was performed on mice to induce osteoporosis, followed by µ-CT scanning of femurs, histological staining, immunohistochemistry analysis of MMP9 and NFATc1, and ELISA of serum BGP, ALP, Ca, and CTXI. The isolated mouse bone marrow mononuclear macrophages (BMMs) were differentiated into osteoclasts under cytokine stimulation. TRAP staining was performed to quantify osteoclasts. The levels of Nfatc1, c-Fos, Acp5, and Ctsk in osteoclasts, m6A level, and the relationships among EGR1, METTL3, and CHI3L1 were analyzed. RESULTS: The EGR1/METTL3/CHI3L1 levels and m6A level were upregulated in osteoporotic mice and the derived BMMs. EGR1 was a transcription factor of METTL3. METTL3 promoted the post-transcriptional regulation of CHI3L1 by increasing m6A methylation. EGR1 downregulation reduced BMMs-differentiated osteoclasts and alleviated OVX-induced osteoporosis by regulating the METTL3/m6A/CHI3L1 axis. CONCLUSION: EGR1 promotes METTL3 transcription and increases m6A-modified CHI3L1 level, thereby stimulating osteoclast differentiation and osteoporosis development.

CHI3L1 as a Prognostic Biomarker and Therapeutic Target in Glioma.

The role of Chitinase-3-like protein 1 (CHI3L1) in tumor progression has been gradually clarified in different kinds of solid tumors. Hence, we aim to elucidate its prognostic value for glioma. In this study, we analyzed RNA sequencing data combined with corresponding clinical information obtained from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Differentially expressed genes (DEGs) were acquired based on CHI3L1 expression profiles and were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Cox regression, least absolute shrinkage and selection operator (LASSO) regression methods, along with a nomogram, were employed to establish a predictive model. Compared with the corresponding non-tumor tissues, CHI3L1 expression was significantly upregulated in various types of solid tumors, correlating with poor clinical outcomes including glioma. GO analysis identified oxidative stress-related genes (ORGs) that were differentially expressed and modulated by CHI3L1, with 11 genes subsequently identified as potential predictors, using Univariate-Cox regression and LASSO regression. In addition, an index of oxidative stress-related genes (ORGI) was established, demonstrating its prognostic value in conjunction with CHI3L1 expression. The aberrant expression of CHI3L1 was proved in glioma patients through immunohistochemistry (IHC). Meanwhile, the knockdown of CHI3L1 inhibited glioma growth in vitro, and real-time Quantitative PCR (qPCR) confirmed decreased ORG expression upon CHI3L1 knockdown, suggesting the potential prognostic value of CHI3L1 as a therapeutic target for glioma.

Inhibition of Amyloid-ß (Aß)-Induced Cognitive Impairment and Neuroinflammation in CHI3L1 Knockout Mice through Downregulation of ERK-PTX3 Pathway.

Several clinical studies reported that the elevated expression of Chitinase-3-like 1 (CHI3L1) was observed in patients suffering from a wide range of diseases: cancer, metabolic, and neurological diseases. However, the role of CHI3L1 in AD is still unclear. Our previous study demonstrated that 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}culfanyl)-N-(4-ethylphenyl)butanamide, a CHI3L1 inhibiting compound, alleviates memory and cognitive impairment and inhibits neuroinflammation in AD mouse models. In this study, we studied the detailed correlation of CHI3L1 and AD using serum from AD patients and using CHI3L1 knockout (KO) mice with Aß infusion (300 pmol/day, 14 days). Serum levels of CHI3L1 were significantly elevated in patients with AD compared to normal subjects, and receiver operating characteristic (ROC) analysis data based on serum analysis suggested that CHI3L1 could be a significant diagnostic reference for AD. To reveal the role of CHI3L1 in AD, we investigated the CHI3L1 deficiency effect on memory impairment in Aß-infused mice and microglial BV-2 cells. In CHI3L1 KO mice, Aß infusion resulted in lower levels of memory dysfunction and neuroinflammation compared to that of WT mice. CHI3L1 deficiency selectively inhibited phosphorylation of ERK and IκB as well as inhibition of neuroinflammation-related factors in vivo and in vitro. On the other hand, treatment with recombinant CHI3L1 increased neuroinflammation-related factors and promoted phosphorylation of IκB except for ERK in vitro. Web-based gene network analysis and our results showed that CHI3L1 is closely correlated with PTX3. Moreover, in AD patients, we found that serum levels of PTX3 were correlated with serum levels of CHI3L1 by Spearman correlation analysis. These results suggest that CHI3L1 deficiency could inhibit AD development by blocking the ERK-dependent PTX3 pathway.

Do Elevated YKL-40 Levels Drive the Immunosuppressive Tumor Microenvironment in Colorectal Cancer? Assessment of the Association of the Expression of YKL-40, MMP-8, IL17A, and PD-L1 with Coexisting Type 2 Diabetes, Obesity, and Active Smoking.

The influence of chitinase-3-like protein 1 (YKL-40 or CHI3L1) expression on the immunological properties of the tumor microenvironment, which may affect the effectiveness of immunotherapy, is currently not sufficiently understood in colorectal cancer (CRC). The aim of this study was to investigate the relationship between YKL-40 expression and the immunological properties of the tumor microenvironment in CRC. We performed in silico analysis, including analysis of immune cell infiltration scores and the immune landscape depending on YKL-40 expression, gene set enrichment analysis (GSEA), and analysis of three Gene Expression Omnibus (GEO) datasets. In 48 CRC tissue homogenates and the surgical margin, we analyzed the expression of YKL-40, MMP8, IL17A, and PD-L1. Moreover, we analyzed the expression of YKL-40 in tissue homogenates retrieved from patients with coexisting diabetes, obesity, and smoking. The expression of YKL-40 was significantly higher in CRC tumor tissue compared to healthy tissue and correlated with MMP-8, IL17A, and PD-L1 expression. In silico analysis revealed an association of YKL-40 with disease recurrence, and GSEA revealed a potential link between elevated YKL-40 expression and immunosuppressive properties of the tumor microenvironment in CRC.

CHI3L1 promotes myocardial fibrosis via regulating lncRNA TUG1/miR-495-3p/ETS1 axis.

Abnormal levels of CHI3L1 and lnc TUG1 are often associated with myocardial fibrosis, and their specific expressions may be closely related to the process of myocardial fibrosis. In addition, CHI3L1 was found to significantly up-regulate the expression of lncTUG1. Therefore, this study further explored the major role of CHI3L1 in regulating the progression of myocardial fibrosis. Myocardial fibrosis in mice was established using an angiotensin (Ang II) model, and the degree of myocardial fibrosis was assessed by qPCR, western blot and pathological techniques. HL-1 cells with overexpression and silencing of CHI3L1 were constructed, and the cell migration ability was detected using the Transwell method. Biological information was used to predict the potential target miRNA of lnc TUG1, and the interaction between them was verified by dual luciferase reporter assay. Using functional rescue assay and the rAAV9 technique, CHI3L1 was verified to affect the fibrotic process of myocardial cells by regulating the lnc TUG1/miR-495-3p/ETS1 axis in vitro and in vivo. The myocardial fibrosis index in the model group was significantly upregulated, and expression of both CHI3L1 and lnc TUG1 was upregulated. Pathological results revealed fibrosis and collagen deposition in the myocardium. Overexpression of lnc TUG1 reversed the inhibitory effect of CHI3L1 silencing on myocardial fibrosis. Mechanistically, CH3L1 upregulates the expression of lnc TUG1, and lnc TUG1 weakens the inhibition of ETS1 through sponge absorption of miR-495-3p, promoting the process of myocardial fibrosis.

Chitinase 3-like 1 induces cancer cell migration in solitary fibrous tumors.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that is diagnosed through the detection of the NAB2-STAT6 fusion gene. SFT rarely progresses to malignant tumors; however, metastasis is exhibited in approximately 20% of patients with SFT. In this study, we found that chitinase 3-like 1 (CHI3L1), which induces cancer cell migration, was upregulated in NIH-3T3 cells that were transfected with the NAB2-STAT6 fusion gene. Moreover, the expression levels of the migration markers MMP2 and MMP9 were increased and the p-Akt level was also upregulated. In addition, it was observed that when CHI3L1 siRNA was transfected into NAB2-STAT6-transfected cells, cell migration and proliferation were reduced. Therefore, this study demonstrated that CHI3L1 activates Akt signaling to induce cell migration.

Cancer stem cell-derived CHI3L1 activates the MAF/CTLA4 signaling pathway to promote immune escape in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) development may be associated with tumor immune escape. This study explores whether the CHI3L1/MAF/CTLA4/S100A4 axis affects immune escape in TNBC through interplay with triple-negative breast cancer stem cells (TN-BCSCs). OBJECTIVE: The aim of this study is to utilize single-cell transcriptome sequencing (scRNA-seq) to uncover the molecular mechanisms by which the CHI3L1/MAF/CTLA4 signaling pathway may mediate immune evasion in triple-negative breast cancer through the interaction between tumor stem cells (CSCs) and immune cells. METHODS: Cell subsets in TNBC tissues were obtained through scRNA-seq, followed by screening differentially expressed genes in TN-BCSCs and B.C.s (CD44+ and CD24-) and predicting the transcription factor regulated by CHI3L1. Effect of CHI3L1 on the stemness phenotype of TNBC cells investigated. Effects of BCSCs-231-derived CHI3L1 on CTLA4 expression in T cells were explored after co-culture of BCSCs-231 cells obtained from microsphere culture of TN-BCSCs with T cells. BCSCs-231-treated T cells were co-cultured with CD8+ T cells to explore the resultant effect on T cell cytotoxicity. An orthotopic B.C. transplanted tumor model in mice with humanized immune systems was constructed, in which the Role of CHI3L1/MAF/CTLA4 in the immune escape of TNBC was explored. RESULTS: Eight cell subsets were found in the TNBC tissues, and the existence of TN-BCSCs was observed in the epithelial cell subset. CHI3L1 was related to the stemness phenotype of TNBC cells. TN-BCSC-derived CHI3L1 increased CTLA4 expression in T cells through MAF, inhibiting CD8+ T cell cytotoxicity and inducing immunosuppression. Furthermore, the CTLA4+ T cells might secrete S100A4 to promote the stemness phenotype of TNBC cells. CONCLUSIONS: TN-BCSC-derived CHI3L1 upregulates CTLA4 expression in T cells through MAF, suppressing the function of CD8+ T cells, which promotes the immune escape of TNBC.

Regulatory role of Chitinase 3-like 1 gene in papillary thyroid carcinoma proved by integration analyses of single-cell sequencing with cohort and experimental validations.

Papillary thyroid carcinoma (PTC) is one of the most common thyroid carcinomas. The gross extrathyroidal extension and extensive metastases of PTC lead to high rates of recurrence and poor clinical outcomes. However, the mechanisms underlying PTC development are poorly understood. In this study, using single-cell RNA sequencing, the transcriptome profiles of two PTC patients were addressed, including PTC1 with low malignancy and good prognosis and PTC2 with high malignancy and poor prognosis. We found that epithelial subcluster Epi02 was the most associated with the malignant development of PTC cells, with which the fold change of Chitinase 3-like 1 (CHI3L1) is on the top of the differentially expressed genes between PTC1 and PTC2 (P < 0.001). However CHI3L1 is rarely investigated in PTC as far. We then studied its role in PTC with a series of experiments. Firstly, qRT-PCR analysis of 14 PTC patients showed that the expression of CHI3L1 was positively correlated with malignancy. In addition, overexpression or silencing of CHI3L1 in TPC-1 cells, a PTC cell line, cultured in vitro showed that the proliferation, invasion, and metastasis of the cells were promoted or alleviated by CHI3L1. Further, immunohistochemistry analysis of 110 PTC cases revealed a significant relationship between CHI3L1 protein expression and PTC progression, especially the T (P < 0.001), N (P < 0.001), M stages (P = 0.007) and gross ETE (P < 0.001). Together, our results prove that CHI3L1 is a positive regulator of malignant development of PTC, and it promotes proliferation, invasion, and metastasis of PTC cells. Our study improves understanding of the molecular mechanisms underlying the progression of PTC and provides new insights for the clinical diagnosis and treatment of PTC.

Chitinase-3-like 1-protein in CSF: a novel biomarker for progression in patients with multiple sclerosis.

BACKGROUND: Chitinase -3-like 1-protein (CHI3L1) is a glycoside secreted by monocytes, microglia, and activated astrocytes. Its distribution in inflammatory lesions denotes its role in astrocytic response to modulate CNS inflammation. In multiple sclerosis (MS), CHI3L1 levels have been found to be influenced by disease severity, activity, and progression. We aimed to measure CSF level of CHI3L1 in patients with MS and correlate its level with disability measures for a possible role as a biomarker for disease progression. METHODS: Fifty-two MS patients (30 relapsing-remitting MS and 22 progressive MS) and thirty-five age and sex-matched healthy controls were included. They all underwent full clinical assessment (including disability and cognitive scales), radiological assessment, and CSF level of CHI3L1. RESULTS: Patients with MS had higher CSF level of CHI3L1 than controls. Patients with progressive forms had higher levels than relapsing forms. There were positive correlations between disease duration, number of attacks, total EDSS, and CSF level of CHI3L1. Patients who had higher level of CSF CHI3L1 showed worse performance in MMSE and BICAMS and more lesions in T2 MRI brain. A cut off value of 154 ng/mL was found between patients with RRMS and PMS patients. CONCLUSION: CHI3L1 can be considered as a biomarker of disease progression. CHI3L1 level increases in progressive MS more than RRMS. Also, high CSF level of CHI3L1 was associated with more disability including motor, cognitive, and radiological aspects.

Potential role of chitinase-3-like protein 1 (CHI3L1/YKL-40) in neurodegeneration and Alzheimer's disease.

Chitinase-3-like protein 1 (CHI3L1/YKL-40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD). In the brain, CHI3L1 is primarily provided by astrocytes and heralds the reactive, neurotoxic state triggered by inflammation and other stress signals. However, how CHI3L1 acts in neuroinflammation or how it contributes to AD and relevant neurodegenerative conditions remains unknown. In peripheral tissues, our group and others have uncovered that CHI3L1 is a master regulator for a wide range of injury and repair events, including the innate immunity pathway that resembles the neuroinflammation process governed by microglia and astrocytes. Based on assessment of current knowledge regarding CHI3L1 biology, we hypothesize that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration. We also recommend future research directions to validate such assertions for better understanding of disease mechanisms.

Chitinase 3-like-1 Expression in the Microenvironment Is Associated with Neutrophil Infiltration in Bladder Cancer.

Bladder cancer is a common cancer with well-established therapeutic strategies. However, recurrence occurs in 50% of patients with non-muscle-invasive bladder cancer, and 20% of patients progress to muscle-invasive bladder cancer. The 5-year survival rate for muscle-invasive bladder cancer patients is disappointingly low, ranging from 36% to 48%. A molecular marker of interest is chitinase 3-like-1 (CHI3L1), which is elevated in various cancers, including bladder cancer. In addition to its role in cancer cells, CHI3L1 also has regulatory abilities in immune cells. Neutrophil infiltration has been shown to positively correlate with overall survival, progression-free survival, and relapse-free survival in bladder cancer patients. However, the relationship between CHI3L1 and neutrophils remain poorly understood. Therefore, this study investigated the relationship between CHI3L1 level and protumor neutrophil infiltration in bladder cancer. We analyzed the GSE128959 dataset and the data of a bladder cancer cohort undergoing chemotherapy. We observed higher expression of CHI3L1 in bladder cancer patients with invasive or chemotherapy-resistance. Our results revealed a positive correlation between CHI3L1 expression and protumor neutrophil infiltration. Elevated CHI3L1 expression was associated with genes which were related to the recruitment and infiltration of neutrophils. Consequently, CHI3L1 may serve as a novel evaluation factor for the degree of neutrophil infiltration in advanced bladder cancer in those scheduled for chemotherapy.

Potential Roles and Future Perspectives of Chitinase 3-like 1 in Macrophage Polarization and the Development of Diseases.

Chitinase-3-like protein 1 (CHI3L1), a chitinase-like protein family member, is a secreted glycoprotein that mediates macrophage polarization, inflammation, apoptosis, angiogenesis, and carcinogenesis. Abnormal CHI3L1 expression has been associated with multiple metabolic and neurological disorders, including diabetes, atherosclerosis, and Alzheimer's disease. Aberrant CHI3L1 expression is also reportedly associated with tumor migration and metastasis, as well as contributions to immune escape, playing important roles in tumor progression. However, the physiological and pathophysiological roles of CHI3L1 in the development of metabolic and neurodegenerative diseases and cancer remain unclear. Understanding the polarization relationship between CHI3L1 and macrophages is crucial for disease progression. Recent research has uncovered the complex mechanisms of CHI3L1 in different diseases, highlighting its close association with macrophage functional polarization. In this article, we review recent findings regarding the various disease types and summarize the relationship between macrophages and CHI3L1. Furthermore, this article also provides a brief overview of the various mechanisms and inhibitors employed to inhibit CHI3L1 and disrupt its interaction with receptors. These endeavors highlight the pivotal roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of metabolic diseases, neurodegenerative diseases, and cancers.

Serum NfL and CHI3L1 for ALS and parkinsonian disorders in the process of diagnosis.

Serum neurofilament light chain (NfL) and chitinase 3-like 1 (CHI3L1, also called YKL-40) concentrations are attractive candidate biomarkers for neurodegenerative disorders, which include amyotrophic lateral sclerosis (ALS) and parkinsonian disorders. We aimed to assess the diagnostic power of serum NfL and CHI3L1 concentrations with regard to the early diagnosis of ALS and Parkinson's disease (PD). We studied 157 individuals, which included 41 healthy controls, 8 patients with ALS mimics, 18 patients initially diagnosed with ALS (ID-ALS), 32 patients late-diagnosed with ALS (LD-ALS), 29 patients with PD, 12 patients with PD mimics, and 17 patients initially diagnosed with atypical parkinsonian disorders (ID-APDs) at the initial stage of diagnosis. Electrochemiluminescence was used to measure the concentrations of serum NfL and CHI3L1, the diagnostic performance of which was assessed using the area under the receiver operating curves (AUCs). The AUCs of serum NfL were 0.90 for discriminating ALS mimics from LD-ALS at the initial stage of diagnosis and 0.89 for discriminating ALS mimics from ALS (LD/ID-ALS). The AUCs of serum NfL were 0.76 for discriminating PD from PD mimics at the initial stage of diagnosis, and 0.80 for discriminating PD from APD. No significant difference existed in serum CHI3L1 concentrations between individuals with suspected ALS or parkinsonism (p = 0.14, and p = 0.44, respectively). Serum NfL had excellent and almost good diagnostic performances for patients with ALS and PD, respectively, at the initial stage of diagnosis, whereas no significant difference existed in serum CHI3L1 between any groups.

Chi3L1 is a therapeutic target in bone metabolism and a potential clinical marker in patients with osteoporosis.

BMP2 is clinically used as an ectopic bone inducer and plays a significant role in bone development, formation, and diseases. Chitinase 3-like 1 protein (Chi3L1) is found in the skeletal system. However, Chi3L1-mediated bone metabolism and aging-related bone erosion via BMP2 signaling have not yet been demonstrated. Herein, Chi3L1 increased BMP2-induced osteoblast differentiation in mesenchymal precursor cells and human primary osteoblasts. Chi3L1KO(-/-) showed abnormal bone development, and primary osteoblasts isolated from Chi3L1KO(-/-) exhibited impaired osteoblast differentiation and maturation. Chi3L1 also potentiated BMP2 signaling and RUNX2 expression in primary osteoblasts. Chi3L1 interacted with BMPRIa, which increased the surface expression of BMPRIa and promoted BMP2 signaling to induce osteoblast differentiation. Chi3L1KO(-/-) mice showed bone formation reduced with a decrease in RUNX2 expression in calvarial defects. Chi3L1KO(-/-) mice exhibited aging-related osteoporotic bone loss with decreases in the levels of RUNX2 and OPG, while serum PYD level and osteoclast number increased. Chi3L1 increased OPG via non-canonical BMP2 signaling in osteoblasts, which suppressed osteoclastogenesis in BMMs. Furthermore, ROC analysis showed that serum Chi3L1 level clinically decreased in osteoporosis patients. Our findings demonstrate that Chi3L1 promotes bone formation, suppresses osteoclastogenesis, and prevents aging-related osteoporosis.