Chitinase 3 like-1 activates the Akt pathway, inducing NF-κB-dependent release of pro-inflammatory cytokines and promoting the proliferative ability in nasopharyngeal carcinoma cells.

BACKGROUND: Chitinase 3 like-1 (CHI3L1) has been reported to function as an oncogene in many types of cancer. However, the biological function of CHI3L1 in nasopharyngeal carcinoma (NPC) remains unknown. METHODS: Differentially expressed genes (DEGs) in NPC tissues in GSE64634 and GSE12452 were downloaded from Gene Expression Omnibus (GEO). CHI3L1, interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) mRNA expression was examined by qRT-PCR. Cell proliferation was evaluated by CCK-8 and EdU incorporation assays. Western blot analysis was used to measure the changes of CHI3L1, nuclear factor-κappaB (NF-κB), and protein kinase B (Akt) pathways. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses were performed using DAVID database. RESULTS: We identified 3 overlapping DEGs using Draw Venn diagram, among which CHI3L1 was chosen for the following analyses. CHI3L1 was upregulated in NPC tissues and cells. CHI3L1 silencing suppressed inflammatory response by inactivating the NF-κB pathway and inhibited cell proliferation in NPC cells. On the contrary, CHI3L1 overexpression induced inflammatory response by activating the NF-κB pathway and promoted cell proliferation in NPC cells. According to GO and KEGG analyses, CHI3L1 positive regulates Akt signaling and is enriched in the PI3K-Akt pathway. CHI3L1 knockdown inhibited the Akt pathway, and CHI3L1 overexpression activated the Akt pathway in NPC cells. Akt overexpression abolished the effects of CHI3L1 knockdown on inflammatory response, NF-κB pathway, and proliferation in NPC cells. On the contrary, Akt knockdown abolished the effects of CHI3L1 overexpression on inflammatory response, NF-κB pathway, and proliferation in NPC cells. CONCLUSION: CHI3L1 knockdown inhibited NF-κB-dependent inflammatory response and promoting proliferation in NPC cells by inactivating the Akt pathway.

Functional variants of the chitinase 3-like 1 gene are associated with clinicopathologic outcomes and progression of prostate cancer.

Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in advanced stages of several cancer types, including prostate cancer (PCa). Impacts of genetic variants of CHI3L1 on PCa development have not yet been investigated. The most common well-studied genetic variations are single-nucleotide polymorphisms (SNPs). Therefore, the objective of this study was to explore associations of CHI3L1 SNPs with both the susceptibility to PCa and its clinicopathological development. Three promoter SNPs, rs6691378 (-1371, G>A), rs10399805 (-247, G>A) and rs4950928 (-131, C>G), and one non-synonymous SNP, rs880633 (+2950, T>C), were analysed using a TaqMan allelic discrimination assay for genotyping in a cohort of 701 PCa patients and 701 healthy controls. Results indicated that there were no significant associations of PCa susceptibility with these four CHI3L1 SNPs. However, among elderly PCa patients (aged >65 years), it was observed that polymorphic variants (GA + AA) of CHI3L1 rs6691378 and 10399805 were significantly linked to reduced risks of several clinicopathological characteristics, including a high Gleason grade, advanced pathologic T stage and tumour cell invasion. Moreover, analyses of The Cancer Genome Atlas database revealed that CHI3L1 expression levels were elevated in PCa tissues compared with normal tissues. Interestingly, higher CHI3L1 expression levels were found to be associated with longer progression-free survival rates in PCa patients. Our findings indicated that levels of CHI3L1 may influence the progression of PCa, and the rs6691378 and 10399805 SNP genetic variants of CHI3L1 are linked to the clinicopathological development of PCa within a Taiwanese population.

The potential roles and mechanisms of Chitinase-3-like-1 in the pathogenesis of type 2-biased airway diseases.

The immune modulation in the epithelium is a protective feature of the epithelial function in the mucosal airways. Dysfunction of the epithelium can lead to chronic allergic airway inflammatory diseases, such as chronic rhinosinusitis with nasal polyps (CRSwNP), allergic rhinitis (AR), and allergic asthma. Chitinase-3-like-1 (CHI3L1) is a key modulator in the epithelium against irritants, pathogens, and allergens and is involved in cancers, autoimmune diseases, neurological disorders, and other chronic diseases. Induction of epithelial cell-derived CHI3L1 is also confirmed to be implicated in the pathogenesis of Th2-related airway diseases like CRSwNP, AR, and allergic asthma, triggering a cascade of subsequent inflammatory reactions leading to the disease development. The techniques that block the biological function of CHI3L1 include small interfering RNA, neutralizing antibodies, and microRNAs and these methods proved to be successful in preclinical and clinical investigation in cancers, autoimmune diseases, asthma, and chronic obstructive pulmonary disease. Therefore, treatment with CHI3L1-blocking methods could open up therapeutic options for allergic airway diseases. This review article discusses the role of epithelial cell-derived CHI3L1 in the development of CRSwNP, AR, and allergic asthma and examines the use of CHI3L1 as a potential therapeutic agent for allergic airway diseases.

Prediction of acute kidney injury incidence following acute type A aortic dissection surgery with novel biomarkers: a prospective observational study.

BACKGROUND: Acute kidney injury (AKI) is a prevalent complication following acute type A aortic dissection (ATAAD) surgery and is closely associated with unfavorable prognostic outcomes. Hence, the development of a robust and efficient diagnostic approach to identify high-risk patients is of paramount importance. METHODS: We conducted a prospective study involving 328 patients who underwent ATAAD surgery at our institution, comprising three distinct cohorts. In addition, 52 patients undergoing alternative cardiopulmonary surgeries and 37 healthy individuals were enrolled as control groups. Employing proteomic analysis, we initially identified plasma proteins potentially linked to AKI occurrence within the plasma proteomic cohort. Subsequent validation was performed in an independent cohort. Utilizing predictors derived from multivariate logistic regression analysis, a nomogram was meticulously formulated and its efficacy was validated in the model construction cohort. RESULTS: Proteomics revealed significant elevation of plasma levels of S100A8/A9, pentraxin 3 (PTX3), and chitinase 3-like 1 (CHI3L1) immediately post-surgery in patients who developed ATAAD surgery-associated AKI (ASA-AKI). Receiver operating characteristic (ROC) curves demonstrated impressive predictive performance of S100A8/A9, PTX3, and CHI3L1 at 0 h post-surgery, yielding area under the curve (AUC) values of 0.823, 0.786, and 0.803, respectively, for ASA-AKI prediction. Furthermore, our findings exhibited positive correlations between plasma levels of S100A8/A9, PTX3, CHI3L1, and urinary neutrophil gelatinase-associated lipocalin (NGAL) at 0 h post-surgery, along with correlations between plasma S100A8/A9, CHI3L1 levels, and the Cleveland Clinic score. A logistic regression model incorporating plasma S100A8/A9, PTX3, CHI3L1 levels, urinary NGAL levels, and the Cleveland Clinic score facilitated the construction of a predictive nomogram for ASA-AKI. This nomogram demonstrated robust discriminative ability, achieving an AUC of 0.963 in the model construction cohort. CONCLUSIONS: Our study underscored the augmentation of plasma S100A8/A9, PTX3, and CHI3L1 levels immediately post-surgery in patients developing ASA-AKI. The incorporation of these three biomarkers, in conjunction with the Cleveland Clinic score and NGAL, into a nomogram demonstrated commendable predictive efficacy. This presents a practical tool for identifying patients at an elevated risk of AKI following ATAAD surgery.

Chitinase Signature in the Plasticity of Neurodegenerative Diseases.

Several reports have pointed out that Chitinases are expressed and secreted by various cell types of central nervous system (CNS), including activated microglia and astrocytes. These cells play a key role in neuroinflammation and in the pathogenesis of many neurodegenerative disorders. Increased levels of Chitinases, in particular Chitotriosidase (CHIT-1) and chitinase-3-like protein 1 (CHI3L1), have been found increased in several neurodegenerative disorders. Although having important biological roles in inflammation, to date, the molecular mechanisms of Chitinase involvement in the pathogenesis of neurodegenerative disorders is not well-elucidated. Several studies showed that some Chitinases could be assumed as markers for diagnosis, prognosis, activity, and severity of a disease and therefore can be helpful in the choice of treatment. However, some studies showed controversial results. This review will discuss the potential of Chitinases in the pathogenesis of some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, to understand their role as distinctive biomarkers of neuronal cell activity during neuroinflammatory processes. Knowledge of the role of Chitinases in neuronal cell activation could allow for the development of new methodologies for downregulating neuroinflammation and consequently for diminishing negative neurological disease outcomes.

CRTH2 Mediates Profibrotic Macrophage Differentiation and Promotes Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a particularly deadly form of pulmonary fibrosis of unknown cause. In patients with IPF, high serum and lung concentrations of CHI3L1 (chitinase 3 like 1) can be detected and are associated with poor survival. However, the roles of CHI3L1 in these diseases have not been fully elucidated. We hypothesize that CHI3L1 interacts with CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) to stimulate profibrotic macrophage differentiation and the development of pulmonary fibrosis and that circulating blood monocytes from patients with IPF are hyperresponsive to CHI3L1-CRTH2 signaling. We used murine pulmonary fibrosis models to investigate the role of CRTH2 in profibrotic macrophage differentiation and fibrosis development and primary human peripheral blood mononuclear cell culture to detect the difference of monocytes in the responses to CHI3L1 stimulation and CRTH2 inhibition between patients with IPF and normal control subjects. Our results showed that null mutation or small-molecule inhibition of CRTH2 prevents the development of pulmonary fibrosis in murine models. Furthermore, CHI3L1 stimulation induces a greater increase in CD206 expression in IPF monocytes than control monocytes. These results demonstrated that monocytes from patients with IPF appear to be hyperresponsive to CHI3L1 stimulation. These studies support targeting the CHI3L1-CRTH2 pathway as a promising therapeutic approach for IPF and that the sensitivity of blood monocytes to CHI3L1-induced profibrotic differentiation may serve as a biomarker that predicts responsiveness to CHI3L1- or CRTH2-based interventions.

Chitinase 3-like 1 is involved in the induction of IL-8 expression by double-stranded RNA in airway epithelial cells.

Viral respiratory infection causes inflammatory lung disease. Chitinase 3-like 1 (CHI3L1) contributes to airway inflammation, but its role in human airway epithelial cells following viral infection is unclear. Thus, we investigated whether CHI3L1 regulates inflammatory responses caused by viral infections in airway epithelial cells. Human bronchial epithelial cells, BEAS-2B, were stimulated with a synthetic analog of viral double-stranded RNA, polyinosinic:polycytidylic acid (poly(I:C)). To confirm the specific role of CHI3L1, CHI3L1 was knocked down in BEAS-2B cells using shRNA lentivirus. The expression of CHI3L1 and proinflammatory cytokines such as IL-8 and phosphorylation of mitogen-activated protein kinase (MAPK) pathways were analyzed. In addition to poly(I:C), BEAS-2B cells were infected with the human respiratory syncytial virus (RSV) A2 strain, and CHI3L1 and IL-8 expression was analyzed. Stimulating the cells with poly(I:C) increased CHI3L1 and IL-8 expression, whereas IL-8 expression was abrogated in CHI3L1 knockdown BEAS-2B cells. Poly(I:C) stimulation of BEAS-2B cells resulted in phosphorylation of MAPK pathways, and inhibition of MAPK pathways significantly abolished IL-8 secretion. Phosphorylation of MAPK pathways was diminished in CHI3L1 knockdown BEAS-2B cells. Infection with RSV increased CHI3L1 and IL-8 expression. IL-8 expression induced by RSV infection was abrogated in CHI3L1 knockdown cells. In conclusion, CHI3L1 may be involved in IL-8 secretion by regulating MAPK pathways during respiratory viral infections in airway epithelial cells.

Associations of Plasma Biomarkers of Inflammation, Fibrosis, and Kidney Tubular Injury With Progression of Diabetic Kidney Disease: A Cohort Study.

RATIONALE & OBJECTIVE: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture nonglomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 594 participants (mean age, 70 years; 53% women) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had diabetes and an estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 at baseline. EXPOSURES: Plasma biomarkers of inflammation/fibrosis (TNFR1 and TNFR2, suPAR, MCP-1, YKL-40) and tubular injury (KIM-1) measured at the baseline visit. OUTCOMES: Incident kidney failure with replacement therapy (KFRT). ANALYTICAL APPROACH: Cox proportional hazards regression and least absolute shrinkage and selection operator regression adjusted for established risk factors for kidney function decline, baseline eGFR, and urinary albumin-creatinine ratio (UACR). RESULTS: A total of 98 KFRT events were observed over a mean of 6.2±3.5 (standard deviation) years of follow-up. Plasma biomarkers were modestly associated with baseline eGFR (correlation coefficients ranging from-0.08 to-0.65) and UACR (0.14 to 0.56). In individual biomarker models adjusted for eGFR, UACR, and established risk factors, hazard ratios for incident KFRT per 2-fold higher biomarker concentrations were 1.52 (95% CI, 1.25-1.84) for plasma KIM-1, 1.54 (95% CI, 1.08-2.21) for TNFR1, 1.91 (95% CI, 1.16-3.14) for TNFR2, and 1.39 (95% CI, 1.05-1.84) for YKL-40. In least absolute shrinkage and selection operator regression models accounting for biomarkers in parallel, plasma KIM-1 and TNFR1 remained associated with incident KFRT. LIMITATIONS: Single biomarker measurement, lack of follow-up eGFR assessments. CONCLUSIONS: Individual plasma markers of inflammation/fibrosis (TNFR1, TNFR2, YKL-40) and tubular injury (KIM-1) were associated with risk of incident KFRT in adults with diabetes and an eGFR<60mL/min/1.73m2 after adjustment for established risk factors.

Assessment of the Association between Genetic Polymorphisms in the CHI3L1 Gene and Asthma Risk.

BACKGROUND: Chitinase 3-like 1 (CHI3L1) is an important factor involved in the development of asthma. This meta-analysis assessed the association of the CHI3L1 polymorphisms rs4950928, rs10399931, rs883125, rs880633, and rs10399805 with asthma risk. METHODS: The literature searches were conducted in PubMed, Web of Science, Wanfang, and China National Knowledge Infrastructure up until September 4, 2021, for relevant studies. Sixteen publications with 18 studies involving 5,005 asthma patients and 9,725 controls were included in this meta-analysis. RESULTS: The meta-analyses showed that among East-Asian subjects, increased asthma risk was associated with CHI3L1 rs4950928 (GG + CG vs. CC: odds ratio [OR] = 1.43, 95% confidence interval [CI]: 1.09-1.88, p = 0.011; GG vs. CG + CC: OR = 1.64, 95% CI: 1.20-2.26, p = 0.002; GG vs. CC: OR = 1.97, 95% CI: 1.41-2.75, p = 0.000; and G vs. C: OR = 1.36, 95% CI: 1.12-1.66, p = 0.002) and rs883125 (G vs. C: OR = 1.42, 95% CI: 1.01-1.99, p = 0.043), whereas CHI3L1 rs10399931 was associated with reduced asthma risk (TT vs. CT + CC: OR = 0.79, 95% CI: 0.64-0.99, p = 0.038; TT vs. CC: OR = 0.77, 95% CI: 0.61-0.98, p = 0.030). In addition, we found an association between CHI3L1 rs4950928 and asthma risk in adult subjects but not children, while CHI3L1 rs883125 was associated with asthma risk in children. CONCLUSION: The CHI3L1 polymorphisms rs4950928, rs10399931, and rs883125 are important genetic factors for asthma among East-Asian subjects.

Chitinase 3-like 1 is not a target antigen in patients with multiple sclerosis.

Autoimmunity to chitinase 3-like 1 (CHI3L1) has recently been reported in hepatic and bowel inflammatory conditions. Considering that CHI3L1 plays a role as prognostic biomarker in multiple sclerosis (MS), here we investigated CHI3L1 as potential autoantigenic target in the disease. We determined serum CHI3L1 autoantibodies by enzyme-linked immunosorbent assay (ELISA) in a cohort of 60 untreated MS patients with different clinical forms of the disease and 20 healthy controls (HC). IgG levels to CHI3L1 were similar between patients with relapsing-remitting MS, primary and secondary progressive MS, and HC. These findings do not support a role for CHI3L1 autoantibodies in MS pathogenesis.

Associations between YKL-40 and markers of disease severity and death in patients with necrotizing soft-tissue infection.

BACKGROUND: Necrotizing soft-tissue infection (NSTI) is a severe and fast-progressing bacterial infection. Prognostic biomarkers may provide valuable information in treatment guidance and decision-making, but none have provided sufficient robustness to have a clinical impact. YKL-40 may reflect the ongoing pathological inflammatory processes more accurately than traditional biomarkers as it is secreted by the activated immune cells, but its prognostic yields in NSTI remains unknown. For this purpose, we investigated the association between plasma YKL-40 and 30-day mortality in patients with NSTI, and assessed its value as a marker of disease severity. METHODS: We determined plasma YKL-40 levels in patients with NSTI (n = 161) and age-sex matched controls (n = 65) upon admission and at day 1, 2 and 3. RESULTS: Baseline plasma YKL-40 was 1191 ng/mL in patients with NSTI compared with 40 ng/mL in controls (p < 0.001). YKL-40 was found to be significantly higher in patients with septic shock (1942 vs. 720 ng/mL, p < 0.001), and in patients receiving renal-replacement therapy (2382 vs. 1041 ng/mL, p < 0.001). YKL-40 correlated with Simplified Acute Physiology Score II (Rho 0.33, p < 0.001). Baseline YKL-40 above 1840 ng/mL was associated with increased risk of 30-day mortality in age-sex-comorbidity adjusted analysis (OR 3.77, 95% CI; 1.59-9.24, p = 0.003), but after further adjustment for Simplified Acute Physiology Score II no association was found between YKL-40 and early mortality. CONCLUSION: High plasma YKL-40 to be associated with disease severity, renal-replacement therapy and risk of death in patients with NSTI. However, YKL-40 is not an independent predictor of 30-day mortality.

N-Glycosylation Regulates Chitinase 3-like-1 and IL-13 Ligand Binding to IL-13 Receptor α2.

Chitinase 3-like-1 (Chi3l1) and IL-13 are both ligands of IL-13 receptor α2 (IL-13Rα2). The binding of the former activates mitogen-activated protein kinase, AKT, and Wnt/ß-catenin signaling, and plays important roles in innate and adaptive immunity, cellular apoptosis, oxidative injury, allergic inflammation, tumor metastasis and wound healing, fibrosis, and repair in the lung. In contrast, the latter binding is largely a decoy event that diminishes the effects of IL-13. Here, we demonstrate that IL-13Rα2 N-glycosylation is a critical determinant of which ligand binds. Structure-function evaluations demonstrated that Chi3l1-IL-13Rα2 binding was increased when sites of N-glycosylation are mutated, and studies with tunicamycin and Peptide:N-glycosidase F (PNGase F) demonstrated that Chi3l1-IL-13Rα2 binding and signaling were increased when N-glycosylation was diminished. In contrast, structure-function experiments demonstrated that IL-13 binding to IL-13Rα2 was dependent on each of the four sites of N-glycosylation in IL-13Rα2, and experiments with tunicamycin and PNGase F demonstrated that IL-13-IL-13Rα2 binding was decreased when IL-13Rα2 N-glycosylation was diminished. Studies with primary lung epithelial cells also demonstrated that Chi3l1 inhibited, whereas IL-13 stimulated, N-glycosylation as evidenced by the ability of Chi3l1 to inhibit and IL-13 to stimulate the subunits of the oligosaccharide complex A and B (STT3A and STT3B). These studies demonstrate that N-glycosylation is a critical determinant of Chi3l1 and IL-13 binding to IL-13Rα2, and highlight the ability of Chi3l1 and IL-13 to alter key elements of the N-glycosylation apparatus in a manner that would augment their respective binding.

Inflammation during Schistosoma haematobium infection and anti-allergy in pre-school-aged children living in a rural endemic area in Zimbabwe.

BACKGROUND: Allergies and autoimmune disorders are less prevalent in areas where parasitic infections are abundant. The relationship between schistosomiasis, Chitinase 3-Like 1 protein (YKL-40), an inflammatory marker, and antinuclear antibodies (ANA), an allergy marker, was investigated in pre-school-aged children (1-5 years old) living in an area endemic to Schistosoma haematobium infection. METHODS: Cross-sectional study including 145 participants, 66 females and 79 males. S. haematobium infection was diagnosed using the urine filtration technique. Levels of YKL-40 and antinuclear antibodies concentrations were determined using enzyme-linked immunosorbent assay. RESULTS: The prevalence of S. haematobium infection was 21.4 % (n = 31) with 114 not infected, 18 with light and 13 with moderate infections. YKL-40 levels were higher in the S. haematobium-infected group than in the uninfected group (P = 0.038). However, S. haematobium infection intensity did not correlate with YKL-40 levels. ANA levels were significantly higher in uninfected children than in infected children (P = 0.028). There was a significant inverse relationship between ANA levels and schistosome infection intensity (r = -0.225, P = 0.016). The correlation between ANA levels and YKL-40 levels was not significant. CONCLUSION: Inflammatory marker in pre-school-aged children living in an area endemic for schistosomiasis indicate YKL-40 as a possible biomarker of S. haematobium infection in pre-school-aged children, warranting further investigations in a longitudinal study.  The study gives an insight into allergy as ANA levels were higher in schistosome-uninfected than infected participants, further studies on allergies are needed.

CONTEXTE: Les allergies et les troubles auto-immunes sont moins répandus dans les régions où les infections parasitaires sont abondantes. La relation entre la schistosomiase, la protéine Chitinase 3-Like 1 (YKL-40), un marqueur antiinflammatoire, et les anticorps antinucléaires (AAN), un marqueur d'allergie, a été étudiée chez des enfants d'âge préscolaire (1 à 5 ans) vivant dans une zone endémique pour l'infection à Schistosoma haematobium. MÉTHODES: Etude transversale portant sur 145 participants, 66 de sexe féminin et 79 de sexe masculin. L'infection à S. haematobium a été diagnostiquée à l'aide de la technique de filtration de l'urine. Les niveaux de YKL-40 et les concentrations d'AAN ont été déterminés en utilisant un dosage immunoenzymatique . RÉSULTATS: La prévalence de l'infection à S. haematobium était de 21,4% (n = 31) avec 114 non infectés, 18 avec des infections légères et 13 avec des infections modérées. Les niveaux de YKL-40 étaient plus élevés dans le groupe infecté par S. haematobium que dans le groupe non infecté (p = 0,038). Cependant, l'intensité de l'infection à S. haematobium ne corrélait pas avec les niveaux de YKL-40. Les niveaux d'AAN étaient significativement plus élevés chez les enfants non infectés que chez les infectés (p = 0,028). Il y avait une relation inverse significative entre les niveaux d'AAN et l'intensité de l'infection schistosomique (r = -0,225, p = 0,016). La corrélation entre les niveaux d'AAN et les niveaux de YKL-40 n'était pas significative. CONCLUSION: Les marqueurs d'inflammation et les marqueurs d'allergie chez les enfants d'âge préscolaire vivant dans une zone endémique pour la schistosomiase indiquent YKL-40 comme biomarqueur possible de l'infection par S. haematobium chez les enfants d'âge préscolaire, ce qui justifie des investigations supplémentaires dans une étude longitudinale. Comme les niveaux d'AAN étaient plus élevés chez les participants non infectés que chez ceux infectés par le schistosome, d'autres études sur les allergies sont nécessaires.

The loss of tolerance to CHI3L1 - A putative role in inflammatory bowel disease?

The incidence of inflammatory bowel disease (IBD) is steadily increasing. IBD is characterized by chronic inflammation of the gastrointestinal tract and is divided into the two main entities Crohn's disease (CD) and ulcerative colitis (UC). Genetic predispositions, environmental factors and a dysregulated immune response are known to be involved at the beginning of IBD. However, their etiopathogenesis is not yet fully understood. Over the last ten years, there has been increasing evidence of the involvement of the member of the 18-glycosylhydrolase family chitinase-3-like protein 1 (CHI3L1) in IBD. CHI3L1 is associated with various diseases such as cancer and chronic inflammatory diseases including rheumatoid arthritis or IBD as well as neurological diseases where it can act as a chemoattractant, mitogen or growth factor. This review will focus on the role of autoimmunity to CHI3L1 in IBD in the context of its expression in inflamed colonic epithelia and interaction with intestinal microbiota. Further, it will provide insights into the interaction of CHI3L1 with different mechanisms of the innate and adaptive immune response in IBD.

Chitinase 3-like 1 drives allergic skin inflammation via Th2 immunity and M2 macrophage activation.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by defective skin barrier and Th2 immune responses. Chitinase 3-like 1 (CHI3L1), also known as breast regression protein 39 (BRP-39) in mice and human homologue YKL-40, plays important roles in Th2 inflammation and allergen sensitization. CHI3L1 has been implicated in a variety of diseases including asthma characterized by inflammation, apoptosis and tissue remodelling, but its role in AD remains elusive. OBJECTIVE: The aim of this study was to investigate the role of CHI3L1 in the development and progression of AD. RESULTS: We investigated YKL-40 levels in the serum and skin of AD patients by ELISA and immunofluorescence, respectively. Using a murine model of AD induced by ovalbumin (OVA), we investigated Th2 immune responses, M2 macrophage activation and skin barrier gene expression using wild-type (WT) and BRP-39 null mutant (BRP-39-/- ) mice. YKL-40 level was significantly increased in serum of AD patients. In addition, both mRNA and protein expression levels of BRP-39 were higher in OVA-sensitized WT mice than in control mice. OVA-sensitized BRP-39-/- mice showed decreased epidermal thickness, lower total serum IgE, Th2 cytokine levels and CD4+ effector T cell populations than OVA-sensitized WT mice. Induction of BRP-39 was dominant in dermal macrophages. BRP-39 deficiency was found to be involved in M2 macrophage activation. Consistently, the YKL-40 level in the skin of AD patients was higher than in normal subjects and it was expressed in dermal macrophages. BRP-39 deficiency attenuated dysregulation of skin barrier and tight junction genes. CONCLUSIONS AND CLINICAL RELEVANCE: These findings demonstrate that CHI3L1 mediates the development of AD induced by OVA, affecting Th2 inflammation, M2 macrophage activation and skin barrier function.

The neuroinflammatory biomarker YKL-40 for neurodegenerative diseases: advances in development.

Introduction: Neuroinflammation is a common pathophysiological mechanism in neurodegenerative diseases (ND). Cerebrospinal fluid (CSF) YKL-40 has recently been candidated as a neuroinflammatory biomarker of ND. Areas covered: We provide an update on the role of CSF YKL-40 as a pathophysiological biomarker of ND. YKL-40 may discriminate Alzheimer's disease (AD) from controls and may predict the progression from the early preclinical to the late dementia stage. In genetic AD, YKL-40 increases decades before the clinical onset. It does not seem a specific biomarker of a certain ND although sporadic Creutzfeldt-Jacob disease shows the highest YKL-40 concentrations. YKL-40 may discriminate between amyotrophic lateral sclerosis (ALS) and ALS-mimics. YKL-40 is potentially associated with the rate of ALS progression. YKL-40 correlates with biomarkers of neuronal injury, large axonal damage and synaptic disruption in various ND. It is not associated with the presence of the APOE-ε4 allele whereas possibly linked to aging, female sex, Hispanic ethnicity and some genetic variants of the chitinase-3-like 1 locus. Expert opinion: There is growing evidence expanding the relevance of CSF YKL-40 as a pathophysiological biomarker for ND. Patients showing high YKL-40 levels might benefit from targeted clinical trials that use compounds acting against neuroinflammatory mechanisms, independently of the initial clinical diagnosis of ND.

A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts.

BACKGROUND: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes. METHODS: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters. RESULTS: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027). CONCLUSIONS: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.

Chitinase 3-like 1 protein plays a critical role in respiratory syncytial virus-induced airway inflammation.

BACKGROUND: Chitinase 3-like 1 protein (CHI3L1) (YKL-40 in humans and breast regression protein [BRP]-39 in mice) is required for optimal allergen sensitization and Th2 inflammation in various chronic inflammatory diseases including asthma. However, the role of CHI3L1 in airway inflammation induced by respiratory viruses has not been investigated. The aim of this study was to investigate the relationship between CHI3L1 and airway inflammation caused by respiratory syncytial virus (RSV) infection. METHODS: We measured YKL-40 levels in human nasopharyngeal aspirate (NPA) from hospitalized children presenting with acute respiratory symptoms. Wild-type (WT) and BRP-39 knockout (KO) C57BL/6 mice were inoculated with live RSV (A2 strain). Bronchoalveolar lavage fluid and lung tissue samples were obtained on day 7 after inoculation to assess lung inflammation, airway reactivity, and expression of cytokines and BRP-39. RESULTS: In human subjects, YKL-40 and IL-13 levels in NPA were higher in children with RSV infection than in control subjects. Expression of BRP-39 and Th2 cytokines, IL-13 in particular, was increased following RSV infection in mice. Airway inflammation caused by RSV infection was reduced in BRP-39 KO mice as compared to WT mice. Th2 cytokine levels were not increased in the lungs of RSV-infected BRP-39 KO mice. BRP-39 regulated M2 macrophage activation in RSV-infected mice. Additionally, treatment with anti-CHI3L1 antibody attenuated airway inflammation and Th2 cytokine production in RSV-infected WT mice. CONCLUSION: These findings suggest that CHI3L1 could contribute to airway inflammation induced by RSV infection. CHI3L1 could be a potential therapeutic candidate for attenuating Th2-associated immunopathology during RSV infection.

Chitinase 3-like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis.

AIM: Chitinase 3-like 1 (CHI3L1), an 18-glycosyl hydrolase-related molecule, is a member of the enzymatically inactive chitinase-like protein family. Serum levels of CHI3L1 are strongly correlated with hepatic fibrosis progression during many liver diseases. Therefore, this protein could be involved in the development of hepatic fibrosis pathology; however, its role has not been elucidated. We aimed to elucidate its role in the pathophysiology of liver fibrosis. METHODS: Chitinase 3-like 1-deficient (Chi3l1-/- ) mice were given carbon tetrachloride twice per week for 4 weeks or fed a methionine choline-deficient diet for 12 weeks to generate mouse liver fibrosis models. Human fibrotic liver tissues were also examined immunohistochemically. RESULTS: In human and mouse fibrotic livers, CHI3L1 expression was mainly localized to hepatic macrophages, and the intrahepatic accumulation of CHI3L1+ macrophages was significantly enhanced compared to that in control livers. In the two mouse models, hepatic fibrosis was significantly ameliorated in Chi3l1-/- mice compared to that in wild-type mice, which was dependent on hepatic macrophages. The accumulation and activation of hepatic macrophages was also significantly suppressed in Chi3l1-/- mice compared to that in wild-type mice. Furthermore, apoptotic hepatic macrophages were significantly increased in Chi3l1-/- mice. Chitinase 3-like 1 was found to inhibit hepatic macrophage apoptosis by suppressing Fas expression and activating Akt signaling in an autocrine manner, which resulted in hepatic macrophage accumulation and activation, exaggerating liver fibrosis. CONCLUSIONS: Chitinase 3-like 1 exacerbates liver fibrosis progression by suppressing apoptosis in hepatic macrophages. Therefore, this might be a potential therapeutic target for the treatment of liver fibrosis.

Chitinase-3-like 1 is a biomarker of acute kidney injury and mortality in paediatric severe malaria.

BACKGROUND: Chitinase-3-like 1 (CHI3L1) is a glycoprotein elevated in paediatric severe malaria, and an emerging urinary biomarker of acute kidney injury (AKI). Based on the hypothesis that elevated CHI3L1 levels in malaria are associated with disease severity, the relationship between plasma CHI3L1 levels, AKI and mortality was investigated in Ugandan children enrolled in a clinical trial evaluating inhaled nitric oxide (iNO) as an adjunctive therapy for severe malaria. METHODS: Plasma CHI3L1 levels were measured daily for 4 days in children admitted to hospital with severe malaria and at day 14 follow up. AKI was defined using the Kidney Disease: Improving Global Outcomes consensus criteria. This is a secondary analysis of a randomized double-blind placebo-controlled trial of iNO versus placebo as an adjunctive therapy for severe malaria. Inclusion criteria were: age 1-10 years, and selected criteria for severe malaria. Exclusion criteria included suspected bacterial meningitis, known chronic illness including renal disease, haemoglobinopathy, or severe malnutrition. iNO was administered by non-rebreather mask for up to 72 h at 80 ppm. RESULTS: CHI3L1 was elevated in patients with AKI and remained higher over hospitalization (p < 0.0001). Admission CHI3L1 levels were elevated in children who died. By multivariable analysis logCHI3L1 levels were associated with increased risk of in-hospital death (relative risk, 95% CI 4.10, 1.32-12.75, p = 0.015) and all-cause 6 month mortality (3.21, 1.47-6.98, p = 0.003) following correction for iNO and AKI. Treatment with iNO was associated with delayed CHI3L1 recovery with a daily decline of 34% in the placebo group versus 29% in the iNO group (p = 0.012). CHI3L1 levels correlated with markers of inflammation (CRP, sTREM-1, CXCL10), endothelial activation (Ang-2, sICAM-1) and intravascular haemolysis (LDH, haem, haemopexin). CONCLUSIONS: CHI3L1 is a novel biomarker of malaria-associated AKI and an independent risk factor for mortality that is associated with well-established pathways of severe malaria pathogenesis including inflammation, endothelial activation, and haemolysis. Trial registration Clinicaltrials.gov, NCT01255215. Registered December 7th 2010.