Expression Of Chitinase 3-like Protein 1 Research Articles

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.

Macrophages regulate healing-associated fibroblasts in diabetic wound

BackgroundRecovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages.Methods and ResultsWe used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1β (IL1β), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice.ConclusionsMacrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

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

Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly upregulated by various inflammatory and immunological diseases, including several cancers, Alzheimer's disease, and atherosclerosis. Several studies have shown that CHI3L1 can be considered as a marker of disease diagnosis, prognosis, disease activity, and severity. In addition, the proinflammatory action of CHI3L1 may be mediated via responses to various proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ. Therefore, CHI3L1 may contribute to a vast array of inflammatory diseases. However, its pathophysiological and pharmacological roles in the development of inflammatory diseases remain unclear. In this article, we review recent findings regarding the roles of CHI3L1 in the development of inflammatory diseases and suggest therapeutic approaches that target CHI3L1.

Role and mechanisms of CHI3L1 in coronary artery lesions in a mouse model of Kawasaki disease-like vasculitis

To explore the role and potential mechanisms of chitinase-3-like protein 1 (CHI3L1) in coronary artery lesions in a mouse model of Kawasaki disease (KD)-like vasculitis. Four-week-old male SPF-grade C57BL/6 mice were randomly divided into a control group and a model group, with 10 mice in each group. The model group mice were intraperitoneally injected with 0.5 mL of lactobacillus casei cell wall extract (LCWE) to establish a mouse model of KD-like vasculitis, while the control group mice were injected with an equal volume of normal saline. The general conditions of the mice were observed on the 3rd, 7th, and 14th day after injection. Changes in coronary artery tissue pathology were observed using hematoxylin-eosin staining. The level of CHI3L1 in mouse serum was measured by enzyme-linked immunosorbent assay. Immunofluorescence staining was used to detect the expression and localization of CHI3L1, von Willebrand factor (vWF), and α-smooth muscle actin (α-SMA) in coronary artery tissue. Western blot analysis was used to detect the expression of CHI3L1, vWF, vascular endothelial cadherin (VE cadherin), Caspase-3, B cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), nuclear factor κB (NF-κB), and phosphorylated NF-κB (p-NF-κB) in coronary artery tissue. The serum level of CHI3L1 in the model group was significantly higher than that in the control group (P<0.05). Compared to the control group, the expression of CHI3L1 in the coronary artery tissue was higher, while the expression of vWF was lower in the model group. The relative expression levels of CHI3L1, Bax, Caspase-3, NF-κB, and p-NF-κB were significantly higher in the model group than in the control group (P<0.05). The relative expression levels of vWF, VE cadherin, and Bcl-2 were lower in the model group than in the control group (P<0.05). In the LCWE-induced mouse model of KD-like vasculitis, the expression levels of CHI3L1 in serum and coronary arteries increase, and it may play a role in coronary artery lesions through endothelial cell apoptosis mediated by inflammatory reactions.

Correlations of special AT-rich sequence binding protein 2 and chitinase-3-like protein-1 with sensitivity to paclitaxel chemotherapy for gastric cancer

Abstract Background: Our objective was to examine the associations between special AT-rich sequence binding protein 2 (SATB2) and chitinase-3-like protein-1 (CHI3L1) and the responsiveness to paclitaxel treatment in individuals with gastric cancer. Methods: From March 2018 to October 2020, our hospital collected gastric cancer samples along with adjacent gastric mucosal tissues located more than 5 cm away from the cancerous margin. These samples were obtained from 90 patients who underwent chemotherapy regimens containing paclitaxel. To assess the rates of positive expression of CHI3L1 and SATB2 in gastric cancer and adjacent tissues, the immunohistochemical streptavidin-peroxidase (SP) technique was utilized. Results: The positive expression rate of CHI3L1 was higher in gastric cancer tissues compared to adjacent tissues, while the positive expression rate of SATB2 was lower (P&lt;0.05). Risk factors that influenced the positive expression of CHI3L1 in gastric cancer tissues included the level of differentiation, tumor-node-metastasis (TNM) stage, and the presence of lymph node metastasis (OR&gt;1, P&lt;0.05). Additionally, the positive expression of SATB2 was also affected by TNM stage and lymph node metastasis, which were identified as risk factors (OR&gt;1, P&lt;0.05). In gastric cancer tissues, there was a negative correlation observed between the expressions of CHI3L1 and SATB2 (r&lt;0, P&lt;0.05). According to the analysis results of Kendall’s tau-b (K), it was found that the presence of CHI3L1 had an inverse relationship with the responsiveness to paclitaxel-based chemotherapy in gastric cancer (r=-0.498, P=0.000), while SATB2 exhibited a positive correlation with the sensitivity (r=0.513, P=0.000). During the 3-year follow-up after chemotherapy, the survival rate was 55.55% (50/90). Conclusions: The findings indicate a strong correlation between SATB2 and CHI3L1 with the TNM stage, lymph node metastasis, response to paclitaxel-based chemotherapy, and the overall survival rate of individuals.

The Potential Roles of CHI3L1 in Failed Autologous Arteriovenous Fistula in End-Stage Renal Disease.

Autologous arteriovenous fistula (AVF) is commonly placed for hemodialysis treatment. Recent studies show that increased baseline serum level of Chitinase-3-like protein 1 (CHI3L1) is independently associated with a higher risk of the early failure of forearm AVFs. However, the changes and mechanisms of CHI3LI in local vascular tissues of failed AVF have not be revealed. This study aims to conduct the expression and mechanism of CHI3L1 in vascular tissues from patients. Immunoreactivity of CHI3L1, matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor-A (VEGF-A) were detected in vascular tissues collected from nine patients with AVF surgery. Due to the significant stenosis clinically, six of the nine patients received arteriovenous fistula reconstruction. The expression differences of CHI3L1 between the initial vascular tissues and failed AVF are significant (P < 0.05). Failed AVF due to stenosis shows intraluminal thrombus, collagen fiber rupture, fibrous connective tissue hyperplasia, tube wall thickening, neovascularization, scattered inflammatory cell infiltration in the tunica media as well as high CHI3L1 expression level, and the expression of MMP-2 (r = 0.9022, P = 0.0139) and VEGF-A (r = 0.8355, P = 0.0393) was positively correlated with CHI3L1. CHI3L1 expression in vascular tissues possibly plays an important role in AVF failure. MMP-2 and VEGF-A may participate in venous stenosis with CHI3L1.

BIOM-15. GLIOBLASTOMA CELLS SHOW ELEVATED CHITINASE 3-LIKE PROTEIN 1 GENE EXPRESSION IN RESPONSE TO HUMAN CEREBROSPINAL FLUID WITH INCREASED MIGRATION AND EPITHELIAL-MESENCHYMAL TRANSITION RELATED ACTIVITY

Abstract Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. GBM tumors proximal to the lateral ventricles have a worse prognosis with multifocality, recurrence, and lower overall survival. Studies suggest this increased aggressiveness is attributed to cerebrospinal fluid (CSF), as we have previously observed transcriptomic changes in GBM cells upon CSF exposure. GlioVis database reveals chitinase 3-like protein 1 (CHI3L1), a glycoprotein secreted by immune and cancer cells, is associated with poor prognosis and co-expressed with pro-inflammatory and tissue remodeling genes. We suggest exposure to CSF elevates CHI3L1 expression, consequently impacting malignancy-associated gene expression in patient-derived GBM lines. We first evaluated if patient CSF influences the expression of CHI3L1. GBM cells were treated with artificial CSF, non-cancer CSF, or cancer CSF for 72 hours. qPCR revealed significant increases in CHI3L1 (p&amp;lt; 0.0001), SPP1, and CD44 expression in cancer CSF groups compared to artificial CSF. CHI3L1 expression at the protein level is also increased by cancer CSF when profiled using Western Blot. Additionally, ELISA results indicated significantly higher levels of CHI3L1 in CSF samples obtained from patients with high-grade tumors compared to non-cancer samples. Next, we assessed if exogenous CHI3L1 stimulates GBM malignancy at the cellular level. An effective concentration of recombinant human CHI3L1 was determined through Alamar Blue assay, showing 500 ng/ml CHI3L1 increases viability in primary patient cell lines compared to non-treated media. Recombinant CHI3L1 also increases cell migration in Transwell assay. qPCR revealed Vimentin (p&amp;lt; 0.001) and Twist (p&amp;lt; 0.0001) expression significantly increases while E-cadherin (p&amp;lt; 0.001) significantly decreases in CHI3L1-treated groups, consistent with EMT and migratory activity. Ultimately, this study shows CHI3L1 is a CSF-induced factor in GBM and could be a therapeutic target as it enhances tumor malignancy by increasing proliferation, migration, and malignancy-promoting gene expression.

The Modeling Analysis and Effect of CHI3L1 and CD31-Marked Microvessel Density in the Occurrence and Development of Cervical Squamous Cell Carcinoma.

Background Chitinase-3-like protein 1 (CHI3Ll) has been identified as a novel tumor marker in several cancers. The objective of this study was to detect the expression of Chitinase-3-like protein 1 (CHI3L1) and CD31-labeled microvessel density (MVD) in cervical squamous cell carcinoma (CSCC) and to assess its prognostic impact. Methods Elivision™ plus immunohistochemical method was used to detect CHI3L1 expression and MVD in different cervical tissues. We analyzed the relationship between CHI3L1 and MVD in CSCC tissues and investigated the relationship between CHI3L1, MVD, and clinicopathological parameters. Univariate and multivariate survival analyses were performed to assess the impact on progression-free survival (PFS) and overall survival (OS). Results The positive expression rate of CHI3L1 protein in CSCC tissues (69.9%, 72/103) was significantly higher than that in high-grade cervical intraepithelial lesions (53.3%, 32/60), low-grade cervical intraepithelial lesions (25%, 15/60), and normal cervical tissues (16.7%, 10/60). MVD values ranged from 6 to 64 in CSCC, and no microvascular formation was observed in normal cervical tissues, high-grade intraepithelial lesions, or low-grade intraepithelial lesions. The high expression of CHI3L1 and MVD was significantly correlated with the invasion depth, differentiation degree, vascular invasion, and lymph node metastasis of CSCC (all P < 0.05). In CSCC, the expression of MVD in the CHI3L1 high-expression group (41.35 ± 9.056) was significantly higher than that in the CHI3L1 low-expression group (23.26 ± 11.000, P < 0.05). On univariate Kaplan–Meier analysis, FIGO stage, tumor diameter, lymph node metastasis, vascular invasion, CHI3L1, and MVD of CSCC were related to the prognosis of PFS and OS (all P < 0.05); however, CHI3L1 and MVD were not independent prognostic factors. Conclusion CHI3L1 may be involved in the progression of cervical cancer. Its high expression can promote neovascularization in the tumor microenvironment. CHI3L1 is a potential therapeutic target in the context of cervical cancer.

Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming.

Background: Chitinase-3-like protein 1 (CHI3L1) is overexpressed in various types of tumors, especially in glioma, and contributes to tumor progression. However, the definite role of CHI3L1 and involved pathway in glioma progression are not completely understood.Methods: CHI3L1 expression in human gliomas and its association with patient survival was determined using enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and public databases. Single-cell RNA-seq was used to characterize the landscape of tumor and myeloid cells. Human proteome microarray assay was applied to identify the binding partners of CHI3L1. Protein-protein interactions were analyzed by co-immunoprecipitation and cellular co-localization. The roles of CHI3L1 in glioma proliferation and invasion were investigated in tumor cell lines by gain- and loss- of function, as well as in vivo animal experiments.Results: CHI3L1 was up-regulated in all disease stages of glioma, which was closely related with tumor survival, growth, and invasion. CHI3L1 was primarily expressed in glioma cells, followed by neutrophils. Moreover, glioma cells with high expression of CHI3L1 were significantly enriched in NF-κB pathway. Pseudo-time trajectory analysis revealed a gradual transition from CHI3L1low to CHI3L1high glioma cells, along with the NF-κB pathway gradually reversed from inhibition to activation. Intriguingly, CHI3L1 binds to actinin alpha 4 (ACTN4) and NFKB1, and enhances the NF-κB signaling pathway by promoting the NF-κB subunit nuclear translocation in glioma cells. Further, CHI3L1 were released into the tumor microenvironment (TME) and interacted with CD44 expressed on tumor-associated macrophages to activate AKT pathway, thereby contributing to M2 macrophage polarization. In addition, CHI3L1 positively correlated to the expression of immune checkpoints, such as CD274 (PD-L1) and HAVCR2 (LAG3), which then remodeled the TME to an immunosuppressive phenotype.Conclusion: Our research revealed that CHI3L1 facilitated NF-κB pathway activation within glioma cells and reprogramed the TME, thereby serving as a promising therapeutic target for glioma.

Effects of chitinase-3-like protein 1 on brain death-induced hepatocyte apoptosis via PAR2-JNK-caspase-3

Hepatocyte apoptosis is a crucial factor affecting liver quality in brain-dead donors. The identification of key molecular proteins involved in brain-death (BD)-induced hepatocyte apoptosis may help determine an effective method for improving the quality of livers from brain-dead donors. In this study, we used in vivo and in vitro models to investigate the role of chitinase-3-like protein 1 (CHI3L1) in promoting liver cell apoptosis after BD. Chitin was used to inhibit CHI3L1 in a rat model of BD. Macrophage polarization of THP-1 cells and hypoxia/reoxygenation (H/R) of LO-2 cells were used to mimic BD-induced cell stress in liver. We found that CHI3L1 played a vital role in promoting liver cell apoptosis. Six hours after BD, CHI3L1 expression was significantly upregulated in liver macrophages and was associated with BD-induced M1 polarization of these cells. In liver cells cultured under H/R conditions, recombinant CHI3L1 activated the protease-activated receptor 2 (PAR2)/c-June N-terminal kinase (JNK) apoptotic pathway and aggravated apoptosis. Compared with the control group, chitin particles inhibited the expression of CHI3L1 in the liver of brain dead rats, thereby reducing activation of the hepatocyte surface receptor, PAR2, and its downstream JNK/caspase-3 signaling pathway, ultimately reducing hepatocyte apoptosis. In conclusion, our results indicate that CHI3L1 relies on a PAR2/JNK-mediated mechanism to promote BD-induced hepatocyte apoptosis.

Chitinase 3-like 1 and neurofilament light chain in CSF and CNS atrophy in MS.

ObjectiveTo investigate cross-sectional associations of CSF levels of neurofilament light chain (NfL) and of the newly emerging marker chitinase 3–like protein 1 (CHI3L1) with brain and spinal cord atrophy, which are established MRI markers of disease activity in MS, to study CHI3L1 and NfL in relapsing (RMS) and progressive MS (PMS), and to assess the expression of CHI3L1 in different cell types.MethodsIn a single-center study, 131 patients with MS (42 RMS and 89 PMS) were assessed for NfL and CHI3L1 concentrations in CSF, MRI-based spinal cord and brain volumetry, MS subtype, age, disease duration, and disability. We included 42 matched healthy controls receiving MRI. CHI3L1 expression of human brain cell types was examined in 2 published single-cell RNA sequencing data sets.ResultsCHI3L1 was associated with spinal cord volume (B = −1.07, 95% CI −2.04 to −0.11, p = 0.029) but not with brain volumes. NfL was associated with brain gray matter (B = −7.3, 95% CI −12.0 to −2.7, p = 0.003) but not with spinal cord volume. CHI3L1 was suitable to differentiate between progressive or relapsing MS (p = 0.015, OR 1.0103, CI for OR 1.002–1.0187), and its gene expression was found in MS-associated microglia and macrophages and in astrocytes of MS brains.ConclusionsNfL and CHI3L1 in CSF were differentially related to brain and spinal cord atrophy. CSF CHI3L1 was associated with spinal cord volume loss and was less affected than NfL by disease duration and age, whereas CSF NfL was associated with brain gray matter atrophy. CSF NfL and CHI3L1 measurement provides complementary information regarding brain and spinal cord volumes.Classification of evidenceThis study provides Class II evidence that CSF CHI3L1 is associated with spinal cord volume loss and that CSF NfL is associated with gray matter atrophy.

Cross-sectional and longitudinal measures of chitinase proteins in amyotrophic lateral sclerosis and expression of CHI3L1 in activated astrocytes

ObjectiveAmyotrophic lateral sclerosis (ALS) is a complex disease with numerous pathological mechanisms resulting in a heterogeneous patient population. Using biomarkers for particular disease mechanisms may enrich a homogeneous subset of...

CHI3L1 results in poor outcome of ovarian cancer by promoting properties of stem-like cells

The role of chitinase-3-like protein 1 (CHI3L1) in ovarian cancer and the possible mechanisms were elucidated. CHI3L1 is a secreted glycoprotein and associated with inflammation, fibrosis, asthma, extracellular tissue remodeling and solid tumors. Our previous study showed CHI3L1 could be a potential prognostic biomarker for epithelial ovarian cancer and could protect cancer cells from apoptosis. Therefore, clinical data and quantitation of CHI3L1 of ovarian cancer patients, tumor spheroid formation, side-population assays, Aldefluor and apoptotic assays, ELISA, RT-PCR, immunoblotting and animal experiments were performed in two ovarian cancer cells lines, OVCAR3 and CA5171, and their CHI3L1-overexpressing and -knockdown transfectants. High expression of CHI3L1 was associated with poor outcome and chemoresistance in ovarian cancer patients. The mRNA expression of CHI3L1 in CA5171 ovarian cancer stem-like cells was 3-fold higher than in CA5171 parental cells. CHI3L1 promoted the properties of ovarian cancer stem-like cells including generating more and larger tumor spheroids and a higher percentage of ALDH+ in tumor cells and promoting resistance to cytotoxic drug-induced apoptosis. CHI3L1 could induce both the Akt (essential) and Erk signaling pathways, and then enhance expression of β-catenin followed by SOX2, and finally promote tumor spheroid formation and other properties of ovarian cancer stem-like cells. OVCAR3 CHI3L1-overexpressing transfectants were more tumorigenic in vivo, whereas CA5171 CHI3L1-knockdown transfectants were not tumorigenic in vivo. CHI3L1 critically enhances the properties of ovarian cancer stem-like cells. CHI3L1 or CHI3L1-regulated signaling pathways and molecules could be potential therapeutic targets in ovarian cancer.

OR-036 Aerobic exercise activates CHI3L1/PAR2 to promote cardiomyocyte proliferation and protect cardiac function in rats with MI

Objective Objectives: The aim of this study is to investigate the changes of protein expression of chitinase-3-like protein 1 (CHI3L1) and its receptor PAR2 (protease-activated receptor 2) after exercise, and the possible mechanism to promote the proliferation of cardiomyocytes and protect MI rats heart.Methods Methods: Using rhCHI3L1 (150 ng/ml), AMPK agonists (AICAR, 50 mM) separately or together administer stimulation for 24 hours.H9C2 cells were divided into control group (H9C2 group), CHI3L1 recombinant protein intervention group (H9C2+rhCHHI3L1), AMPK agonist intervention group (H9C2+AICAR), and CHI3L1 recombinant protein and AMPK agonist combined intervention group (H9C2+rhCHI3L1+AICAR).SD rats were subjected to left anterior descending(LAD) coronary artery ligation to prepare MI models and randomly divided into sham operation group (S), myocardial infarction group (MI), myocardial infarction aerobic exercise group (ME), and injection of PAR-2 blocker agent (FSLLRY-amide) was divided into 7-day PAR2 blocker injection group (7d+FS), MI 7-day saline injection group (7d+SA), MI 14 days PAR2 blocker injection group (14d+FS), MI 14-day saline injection group (14d+SA). One week after surgery, the ME group were subjected to oneweekadaptively exercise followed by four weeks aerobic exercise.At the end of the training, the rats were intraperitoneally anesthetized the next day. Hemodynamic measurements of LVEDP, ±dp/dt max, and LVSP were used to evaluate cardiac function.The protein levels of CHI3L1/PAR2, pPI3K/PI3K, pAKT/AKT, pERK/ERK and Cyclin D1 in H9C2 and rat hearts were determined by Western blotting. The proliferation of H9C2 was detected by CCK-8. The proliferation of H9C2 and cardiac tissue was observed by immunofluorescence. Masson staining was used to observe myocardial collagen volume percent (CFV%).Results Results: Compared with H9C2 control group, the expression of CHI3L1, pPI3K/PI3K, pAKT/AKT, pERK/ERK, and Cyclin D1 protein increased significantly after rhCHI3L1 and AICAR intervention for 24 h, respectively. CCK-8 test and immunofluorescence indicated that H9C2 had significant proliferation effect. In MI rat heart, compared with MI group, the expression of CHI3L1, pPI3K/PI3K, pAKT/AKT, pERK/ERK and Cyclin D1 protein in ME group increased significantly, the number of cell proliferation increased, and LVEDP significantly decreased, ±dp/dt max, LVSP significantly increased, and the CFV% decreased significantly.Conclusions Conclusion: Exercise may promote cardiomyocyte proliferation and improve cardiac function in MI rats by activating the CHI3L1/PAR2-PI3K-AKT-ERK signaling pathway.

Association of the Polymorphisms and Plasma Level of CHI3L1 with Alzheimer’s Disease in the Chinese Han Population: A Case-Control Study

Objective: To investigate whether the polymorphisms and plasma level of chitinase-3-like protein 1 (CHI3L1) are associated with Alzheimer’s disease (AD) in the Chinese Han population. Methods: A total of 166 patients who were initially diagnosed with AD were enrolled as the case group, and 184 healthy subjects were recruited as the healthy controls. TaqMan® SNP genotyping assays were applied for the genotyping of rs4950928, rs10399931 and rs6691378. The plasma level of CHI3L1 was determined by enzyme-linked immunosorbent assay. Results: The CG+GG genotype of rs4950928 C>G is a protective factor for AD and could effectively reduce the severity of AD. Patients with the CT+TT genotype of rs10399931 C>T had a significantly increased risk of AD, and it apparently aggravated the severity of AD. Moreover, the plasma CHI3L1 level in AD patients was significantly higher than that in healthy controls, which was increased with the severity of AD. A Kaplan-Meier survival curve showed that significant differences in 5-year survival rates were found in AD patients in different genotypes of CHI3L1 rs4950928 C>G and rs10399931 C>T. The AD patients and healthy controls who carried the CG+GG genotype of rs4950928 C>G had lower plasma CHI3L1 levels than CC genotype carriers. However, the CT+TT genotype of rs10399931 in the AD patients had an elevated plasma level of CHI3L1 as compared with the CC genotype. Binary logistic regression analysis showed that the plasma level of CHI3L1, the CC genotype of rs4950928 C>G and the CT+TT genotype of rs10399931 C>T were risk factors for AD. Conclusion: Polymorphisms of the CHI3L1 gene (rs4950928 C>G and rs10399931 C>T) are associated with the risk and prognosis of AD and can affect the expression of CHI3L1 in plasma.

Identification of proteins highly expressed in uterine fluid from mice with hydrometra

Estrogen receptor alpha (ERα) is an important regulator of the estrous cycle and mice with global ERα deletion, as well as some conditional knockout mouse lines, have an interruption in the estrous cycle. In this study we observed that conditional ERα knockout mice where the Cre gene is regulated by the rat insulin promoter (RIP), RIP-Cre/ERαKO mice, have a 3.7-fold increase in serum 17β-estradiol levels, blocked estrous cycle, and develop a fluid-filled uterus (hydrometra). Using a proteomics approach, we identified three proteins, lactoferrin, complement C3 and chitinase 3-like protein 1 (CHI3L1), as highly expressed proteins in hydrometra fluid. The mRNA levels of the corresponding genes were more than 50-fold higher in RIP-Cre/ERαKO uterus compared to controls. High expression of CHI3L1 in the uterine fluid was not reflected as elevated levels in the serum. The high expression of lactoferrin, complement C3 and CHI3L1 in the uterine fluid, in association with elevated estrogen levels, prompted us to address if the expression of these genes is related to reproduction. However, gonadotropin treatment of mice reduced the uterine expression of these genes in a model of in vitro fertilization. Our findings identify lactoferrin, complement C3 and CHI3L1 as highly expressed proteins in hydrometra fluid in association with chronically elevated serum estradiol levels.

Role for mammalian chitinase 3-like protein 1 in traumatic brain injury.

Traumatic brain injury (TBI) is accompanied by inflammatory infiltrates and CNS tissue response. The astrocytosis associated with TBI has been proposed to have both beneficial and detrimental effects on surviving neural tissue. We recently observed prominent astrocytic expression of YKL-40/chitinase 3-like protein 1 (CHI3L1) associated with severity of brain injury. The physiological role of CHI3L1 in the CNS is unknown; however, its distribution at the perimeter of contusions and temporal course of expression suggested that in TBI it might be an important component of the astrocytic response to modulate CNS inflammation. To address this hypothesis, we used serially sectioned brains to quantitatively compare the neuropathological outcomes of TBI produced by controlled cortical impact in wild type (WT) and chi3l1 knockout (KO) mice where the murine YKL-40 homologue, breast regression protein 39 (BRP-39/CHI3l1), had been homozygously disrupted. At 21 days post-injury, chi3l1 KO mice displayed greater astrocytosis (increased GFAP staining) in the hemispheres ipsilateral and contralateral to impact compared with WT mice. Similarly, Iba1 expression as a measure of microglial/macrophage response was significantly increased in chi3l1 KO compared with WT in the hemisphere contralateral to impact. We conclude that astrocytic expression of CHI3L1 limits the extent of both astrocytic and microglial/macrophage facets of neuroinflammation and suggests a novel potential therapeutic target for modulating neuroinflammation.

Evaluation of CHI3L-1 and CHIT-1 Expression in Differentiated and Polarized Macrophages

Chitinase 3-like protein 1 (CHI3L-1) and chitotriosidase (CHIT-1) are members of the chitinase family. CHI3L-1 is a newly recognized protein that is secreted by activated macrophages and neutrophils and expressed in a broad spectrum of inflammatory conditions and cancers. In human plasma, CHIT-1 activity has been proposed as a biochemical marker of macrophage activation. Although CHI3L-1 expression in inflammation is under examination, little is known regarding its regulation during macrophages' full maturation and polarization. In this study, we compared CHI3L-1 and CHIT-1 modulation during monocyte to macrophage transition and polarization. Gene expression analysis was investigated by real-time PCR. We found that during the maturation of monocytes into macrophages, the expression of both CHI3L-1 and CHIT-1 increased exponentially over time. Additionally, we observed a different regulation of CHI3L-1 and CHIT-1 in undifferentiated monocytes under stimulation with lipopolysaccharide, interferon-γ, and interleukin-4, at the same concentration used to polarize macrophages. Our finding suggests that in the immune response, the role of CHI3L-1 and CHIT-1 is not restricted to innate immunity, but they are also protagonists in acquired immunity.