Chitinase 3-like 1 Research Articles

Changes in serum chitinase 3‐like 1 levels correlate with changes in liver fibrosis measured by two established quantitative methods in chronic hepatitis B patients following antiviral therapy

Non-invasive assessment of changes in liver fibrosis is still an unmet medical need in the era of antiviral therapy. Therefore, we explore whether chitinase 3-like 1 (CHI3L1), a serum marker of liver fibrosis, can be used as a non-invasive surrogate marker of fibrosis change during treatment. We correlated serum CHI3L1 levels with liver tissue collagen proportionate area (CPA) in a cohort of 131 patients with chronic hepatitis B (CHB) receiving entecavir-based antiviral therapy for 78weeks. In addition, we compared this marker with the liver stiffness measurement (LSM). Multivariate regression analyses were undertaken to determine the clinical factors associated with the CHI3L1 levels. Before treatment, correlation analysis showed that there were positive correlations between CHI3L1 levels and the CPA (r = 0.351, P < 0.001), and between CHI3L1 and LSM (r = 0.412, P < 0.001). After 78weeks treatment, serum CHI3L1 levels decreased compared with that at baseline (87.8 vs. 69.6ng/mL, P < 0.001), and CHI3L1 levels were also correlated with CPA (r = 0.293, P = 0.001) and LSM (r = 0.443, P < 0.001). Furthermore, there were positive correlations between the changes in CHI3L1 and CPA (r = 0.366, P<0.001), and changes in CHI3L1 and LSM (r = 0.438, P<0.001). Multivariate regression analyses indicated that CPA values were related with pre- (β = 5.450, P = 0.019) and post-treatment CHI3L1 levels (β = 7.460, P = 0.023). Chitinase 3-like 1 is not only a useful non-invasive marker for the assessment of liver fibrosis in CHB patients before treatment, but also a potential useful marker for monitoring the change in liver fibrosis during therapy.

Defining active progressive multiple sclerosis

Background: It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS). Objective: To compare CSF biomarkers in active and inactive progressive MS according to consensus criteria. Methods: Neurofilament light chain (NFL), myelin basic protein (MBP), IgG-index, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), chemokine CXCL13, terminal complement complex, leukocyte counts and nitric oxide metabolites were measured in primary (n = 26) and secondary progressive MS (n = 26) and healthy controls (n = 24). Results: Progressive MS patients had higher CSF cell counts, IgG-index, CHI3L1, MMP-9, CXCL13, NFL and MBP concentrations. Active patients were younger and had higher NFL, CXCL13 and MMP-9 concentrations than inactive patients. Patients with active disease according to consensus criteria or detectable CXCL13 or MMP-9 in CSF were defined as having combined active progressive MS. These patients had increased CSF cell counts, IgG-index and MBP, NFL and CHI3L1 concentrations. Combined inactive patients only had increased IgG-index and MBP concentrations. Conclusion: Patients with combined active progressive MS show evidence of inflammation, demyelination and neuronal/axonal damage, whereas the remaining patients mainly show evidence of active demyelination. This challenges the idea that neurodegeneration independent of inflammation is crucial in disease progression.

Circulating tumor cell interactions with macrophages: implications for biology and treatment.

Cancer and metastasis are closely associated with inflammation. Macrophages are important effector cells in enhancing tumor proliferation, invasion and providing protection against the immune system. Despite advanced knowledge of tumor-macrophage interactions, the role of macrophages in emergence and invasion of circulating tumor cells (CTCs) is not known. A series of six CTC cell lines have been derived from blood of patients with extensive disease small cell lung cancer (ED-SCLC) in our lab, most likely representing a homogenous cell population of the actual metastasis-initiating cells (MIC) of CTCs. SCLC has an unfavorable prognosis due to rapid dissemination and early chemoresistant relapses. SCLC CTCs recruit macrophages and elicit secretion of various cytokines and the six CTC lines express chitinase-3-like-1 (CHI3L1), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) in abundance. CHI3L1 is cytokine/growth factor expressed in inflammation and cancer and found to be correlated to metastasis and a dismal prognosis. In conclusion, SCLC CTCs have acquired the essential means for aggressiveness and invasion in a tumor microenvironment specifically shaped by macrophages and inflammation.

Preconditioning with Lipopolysaccharide or Lipoteichoic Acid Protects against Staphylococcus aureus Mammary Infection in Mice.

Staphylococcus aureus is one of the most causative agents of mastitis and is associated with chronic udder infections. The persistency of the pathogen is believed to be the result of an insufficient triggering of local inflammatory signaling. In this study, the preclinical mastitis model was used, aiming to evaluate if lipopolysaccharide (LPS) or lipoteichoic acid (LTA) preconditioning could aid the host in more effectively clearing or at least limiting a subsequent S. aureus infection. A prototypic Gram-negative virulence factor, i.e., LPS and Gram-positive virulence factor, i.e., LTA were screened whether they were able to boost the local immune compartment. Compared to S. aureus-induced inflammation, both toxins had a remarkable high potency to efficiently induce two novel selected innate immunity biomarkers i.e., lipocalin 2 (LCN2) and chitinase 3-like 1 (CHI3L1). When combining mammary inoculation of LPS or LTA prior to a local S. aureus infection, we were able to modulate the innate immune response, reduce local bacterial loads, and induce either LCN2 or CHI3L1 at 24 h post-infection. Clodronate depletion of mammary macrophages also identified that macrophages contribute only to a limited extend to the LPS/LTA-induced immunomodulation upon S. aureus infection. Based on histological neutrophil influx evaluation, concomitant local cytokine profiles and LCN2/CHI3L1 patterns, the macrophage-independent signaling plays a major role in the LPS- or LTA-pretreated S. aureus-infected mouse mammary gland. Our results highlight the importance of a vigilant microenvironment during the innate immune response of the mammary gland and offer novel insights for new approaches concerning effective immunomodulation against a local bacterial infection.

Breast Regression Protein-39/Chitinase 3-Like 1 Promotes Renal Fibrosis after Kidney Injury via Activation of Myofibroblasts.

The normal response to kidney injury includes a robust inflammatory infiltrate of PMNs and macrophages. We previously showed that the small secreted protein breast regression protein-39 (BRP-39), also known as chitinase 3-like 1 (CHI3L1) and encoded by the Chi3l1 gene, is expressed at high levels by macrophages during the early stages of kidney repair and promotes tubular cell survival via IL-13 receptor α2 (IL13Rα2)-mediated signaling. Here, we investigated the role of BRP-39 in profibrotic responses after AKI. In wild-type mice, failure to resolve tubular injury after unilateral ischemia-reperfusion injury (U-IRI) led to sustained low-level Chi3l1 mRNA expression by renal cells and promoted macrophage persistence and severe interstitial fibrosis. Analysis of macrophages isolated from wild-type kidneys 14 days after U-IRI revealed high-level expression of the profibrotic BRP-39 receptor Ptgdr2/Crth2 and expression of the profibrotic markers Lgals3, Pdgfb, Egf, and Tgfb In comparison, injured kidneys from mice lacking BRP-39 had significantly fewer macrophages, reduced expression of profibrotic growth factors, and decreased accumulation of extracellular matrix. BRP-39 depletion did not affect myofibroblast accumulation but did attenuate myofibroblast expression of Col1a1, Col3a1, and Fn1 Together, these results identify BRP-39 as an important activator of macrophage-myofibroblast crosstalk and profibrotic signaling in the setting of maladaptive kidney repair.

Chitinase 3-Like-1-Deficient Splenocytes Deteriorated the Pathogenesis of Acute Graft-Versus-Host Disease via Regulating Differentiation of Tfh Cells.

Acute graft-versus-host disease (aGVHD) is an intractable complication in transplant patients, limiting the efficacy of this therapy. Chitinase 3-like-1 (CHI3L1), a member of the glycosyl hydrolase 18 family that lacks chitinase activity, plays a critical role in a variety of inflammatory diseases. Here, we investigated the in vitro and in vivo effects of CHI3L1 on the development of aGVHD. In this study, mixed lymphocyte reactions (MLR) in vitro showed that CHI3L1 deficiency in CD4+ T cell promoted the production of interferon (IFN)-γ and T follicular helper (Tfh)-related cytokines such as interleukin-6 (IL-6) and interleukin-21 (IL-21). Meanwhile, the inducible Tfh cell population increased remarkably in CHI3L1-KO CD4+ T cells' induction group, compared with WT group. Then, in the murine acute GVHD model, we found that CHI3L1 deficiency in donor splenocytes dramatically increased the severity of aGVHD through enhancing Tfh cell differentiation. Moreover, at mRNA and protein levels, we defined several molecules that may account for the enhanced ability of CHI3L1-KO splenocytes to migrate into target organs and produce IFN-γ and Tfh-related cytokines and chemokines, such as IL-6, IL-21, and CXCL13. Expression of inducible co-stimulator (ICOS) and B cell lymphoma 6 (Bcl6) increased in the skin, the intestine, the lung, and the liver from CHI3L1-KO splenocyte-treated aGVHD mice. Therefore, these results strongly imply that CHI3L1 levels in donor cells may be related to the risk of aGVHD and targeting CHI3L1 represents a novel therapeutic strategy for controlling aGVHD progression.

CHI3L1 regulation of inflammation and the effects on osteogenesis in a Staphylococcus aureus-induced murine model of osteomyelitis.

Osteomyelitis is an inflammation of the bone and bone marrow that occurs as a consequence of infections mainly attributed to Staphylococcus aureus. In a previous study, we found that expression of the chitinase 3-like 1 (CHI3L1) gene affected mineralization of MC3T3-E1 cells infected with S. aureus and there was increased expression of CHI3L1 in the blood of osteomyelitis patients. In the present study, to further investigate the role of CHI3L1 in osteomyelitis, we developed an S. aureus-induced murine model of the disease. We found that the expression of CHI3L1 was significantly up-regulated in femurs of mice infected with S. aureus compared with mice inoculated with a PBS control. To investigate these results further, we performed a CHI3L1 knock-down by lentivirus-mediated RNA interference in mice. Micro-computed tomography of infected femurs revealed that S. aureus triggers profound alterations in bone turnover, and femurs of CHI3L1 short hairpin RNA (shRNA-CHI3L1)-injected mice infected with S. aureus have significantly less cortical bone destruction when compared with control mice infected with S. aureus. Inhibition of CHI3L1 also decreased inflammation by reducing levels of proinflammatory cytokines and promoted the process of osteogenesis. The Notch signaling pathway has been shown to play an important role in modulating the differentiation of osteoblasts and osteoclasts. Our study showed that Notch1, Jagged1 and Hes1 expression significantly decreased in mice infected with S. aureus compared with the control, and shRNA-CHI3L1 could increase their level in S. aureus-infected mice. This research indicates that inhibition of CHI3L1 can reduce the debilitating effects of S. aureus in a murine model of osteomyelitis.

Screening critical genes associated with malignant glioma using bioinformatics analysis.

Malignant gliomas are high-grade gliomas, which are derived from glial cells in the spine or brain. To examine the mechanisms underlying malignant gliomas in the present study, the expression profile of GSE54004, which included 12 grade II astrocytomas, 33 grade III astrocytomas and 98 grade IV astrocytomas, was downloaded from the Gene Expression Omnibus. Using the Limma package in R, the differentially expressed genes (DEGs) in grade III, vs. grade II astrocytoma, grade IV, vs. grade II astrocytoma, and grade IV, vs. grade III astrocytoma were analyzed. Venn diagram analysis and enrichment analyses were performed separately for the DEGs using VennPlex software and the Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction (PPI) networks were visualized using Cytoscape software, and subsequent module analysis of the PPI networks was performed using the ClusterONE tool. Finally, glioma-associated genes and glioma marker genes among the DEGs were identified using the CTD database. A total of 27, 1,446 and 776 DEGs were screened for the grade III, vs. grade II, grade IV, vs. grade II, and grade IV, vs. grade III astrocytoma comparison groups, respectively. Functional enrichment analyses showed that matrix metalloproteinase 9 (MMP9) and chitinase 3-like 1 (CHI3L1) were enriched in the extracellular matrix and extracellular matrix structural constituent, respectively. In the PPI networks, annexin A1 (ANXA1) had a higher degree and MMP9 had interactions with vascular endothelial growth factor A (VEGFA). There were 10 common glioma marker genes between the grade IV, vs. grade II and the grade IV, vs. grade III comparison groups, including MMP9, CHI3L1, VEGFA and S100 calcium binding protein A4 (S100A4). This suggested that MMP9, CHI3L1, VEGFA, S100A4 and ANXA1 may be involved in the progression of malignant gliomas.

Chitinase 3-like-1 deficient donor splenocytes accentuated the pathogenesis of acute graft-versus-host diseases through regulating T cell expansion and type I inflammation

Acute graft-versus-host disease (aGVHD) is a major complication following transplantation, limiting the success of this therapy. Chitinase 3-like-1 (CHI3L1), a member of the glycosyl hydrolase 18 family, plays a critical role in bacterial infections, allergic disease and a variety of malignancies. Here, we investigated whether CHI3L1 could affect the pathogenesis of aGVHD in a mouse allo-HCT model. In this study, we show that CHI3L1 deficiency in donor T cells increased the severity of aGVHD through enhancing systemic and local inflammation. In addition, we found that aGVHD induced by CHI3L1-knockout (CHI3L1-KO) donors resulted in massive expansion of donor CD3+ T cells, release of Th1-related cytokines and chemokines, and significant inhibition of CD4+CD25+Foxp3+ regulatory T cells (Tregs) without changing the suppressive ability of donor Tregs remarkably. Expression of PERK1/2 and PAkt increased both in the skin and intestine from CHI3L1-KO splenocytes-treated aGVHD mice. Moreover, at mRNA and protein levels, we defined several molecules that may account for the enhanced ability of CHI3L1-KO splenocytes to migrate into target organs and produce Th1-related cytokines and chemokines, such as CXCL9, CXCL11, IFN-γ and TNF-α. Therefore, these results imply that CHI3L1 levels in donor cells may be related to the risk of aGVHD and targeting CHI3L1 may be a promising clinical strategy to control aGVHD.

P382 A panel of serum markers for early detection of endoscopic healing with infliximab in patients with ulcerative colitis

Background: The need for surrogate markers to detect endoscopic healing in inflammatory bowel disease (IBD) is imminent. Previously, neutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 (NGAL-MMP-9) complex was found to be superior to CRP for detection of endoscopic healing with infliximab (IFX) in patients with ulcerative colitis (UC)[1]. Both cathelicidin LL-37 and chitinase 3-like 1 (CHI3L1) are secreted by neutrophils and were previously associated with IBD [2,3]. The aim of this study was to investigate whether LL-37 and/or CHI3L1 could improve detection of endoscopic healing with IFX in UC patients. Methods: Serum samples were obtained from 145 UC patients (41% female, median [IQR] age 41.3 [30.8–51.9] years) who underwent endoscopy following IFX initiation and from 75 controls (56% female, median [IQR] age 33.6 [29.2–51.8] years). Endoscopic healing with IFX was defined as a Mayo endoscopic subscore of 0 or 1. CRP, NGAL-MMP-9 and neutrophils were previously determined [1], and LL-37 and CHI3L1 were measured with ELISA (Hycult Biotech and R&D systems, respectively). For all markers, optimal cut-offs were determined with ROC analysis and binary variables were entered in a logistic regression model to generate the Ulcerative Colitis Response Index (UCRI). Non-parametric tests were performed and p-values <0.05 were considered significant. Results: Median (IQR) time to serum sampling after IFX was 8.2 (6.0–14.0) weeks. 83 patients (57%) had endoscopic healing, whereas 62 patients (43%) did not. Median [IQR] LL-37 levels (ng/ml) were significantly lower in healers (24.3 [16.1–41.4]) compared to non-healers (37.3 [24.0–53.8], p=0.002), but remained elevated compared to controls (16.7 [10.2–27.1]; p<0.001). Median [IQR] CHI3L1 levels (ng/ml) were significantly lower in healers (20.9 [14.3–34.4]) compared to both non-healers (30.0 [22.7–53.9], p<0.001) and controls (31.9 [19.6–48.6], p=0.003). UCRI consisted of CRP (Odds ratio [95% CI] 3.3 [1.4–7.5]), CHI3L1 (3.1 [1.3–7.7]), neutrophils (4.9 [2.1–11.2]) and LL-37 (2.5 [1.0–6.4]). The AUC of UCRI was 0.83 and Q1 (0.0–2.6) was able to discriminate healing with 54% sensitivity, 92% specificity, 60% NPV and 90% PPV, whereas Q4 (7.2–9.8) was able to discriminate non-healing with 37% sensitivity, 95% specificity, 67% NPV and 85% PPV. Finally, UCRI could detect endoscopic healing as early as 3 weeks after IFX initiation (Hazard ratio [95% CI] 4.1 [2.6–6.5]). Conclusions: In the search for surrogate markers of endoscopic healing, UCRI was shown to accurately identify UC patients who fail to achieve healing with IFX and may help in early decision making to therapy switch.

Correlation of Chitinase 3-Like 1 Single Nucleotide Polymorphisms with Hepatocellular Carcinoma in Taiwan

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death in Taiwan. Multiple risk factors, such as chronic hepatitis B or C virus infection, carcinogen exposure, cirrhosis, and various single-nucleotide polymorphisms (SNPs), are considered to contribute to hepatocarcinogenesis. Chitinase-3-like protein 1 (CHI3L1), a biomarker implicated in inflammation and tissue remodeling, plays a promoting role in angiogenesis, antiapoptosis, and cell proliferation. This study investigated the role of CHI3L1 SNPs in HCC susceptibility and clinicopathology. Real-time polymerase chain reaction was used to analyze four SNPs of CHI3L1 in 343 patients with HCC and 686 cancer-free controls. We found associations with HCC susceptibility in CHI3L1 rs880633 polymorphism carriers with genotypes (TC+CC). We observed that HCC patients had lower frequencies of CHI3L1 rs6691378 polymorphisms with the variant genotype GA+AA than the wild-type carriers with distant metastasis and positive HBsAg did. In 200 HBsAg negative HCC patients, we observed that the CHI3L1 rs4950928 polymorphisms carriers with the variant genotype CG+GG had higher frequencies of vascular invasion. Finally, carriers of CHI3L1 rs6691378 and 10399805 polymorphisms with the variant genotypes GA+AA showed lower levels of alpha-fetoprotein in HCC laboratory status. In conclusion, our results indicate that patients with CHI3L1 rs880633 variant genotypes TC+CC are at a higher risk of HCC. CHI3L1 polymorphisms rs880633 or rs4950928 may be potential candidates for predicting poor HCC prognosis and clinical status.

Chitinase 3-like 1 is associated with the response to interferon-beta treatment in multiple sclerosis

Chitinase 3-like 1 (CHI3L1) plays a prognostic role in patients with multiple sclerosis (MS). Here, we investigated a potential association between CHI3L1 and the response to interferon-beta (IFNβ) and glatiramer acetate (GA). Serum CHI3L1 levels were measured by ELISA in 117 relapsing-remitting MS (RRMS) patients, 76 IFNβ-treated and 41 GA-treated patients. CHI3L1 levels were increased by GA (p=0.014) but unchanged by IFNβ (p=0.830). CHI3L1 was associated with IFNβ response and levels were higher in non-responder group (p=0.020), while GA showed no responder effect (p=0.943). These results suggest a role for CHI3L1 as response biomarker to IFNβ in RRMS patients.

Comparison of the Adipose and Luminal Mammary Gland Compartment as Orthotopic Inoculation Sites in a 4T1-Based Immunocompetent Preclinical Model for Triple-Negative Breast Cancer.

Breast tumorigenesis is classically studied in mice by inoculating tumor cells in the fat pad, the adipose compartment of the mammary gland. Alternatively, the mammary ducts, which constitute the luminal mammary gland compartment, also provide a suitable inoculation site to induce breast cancer in murine models. The microenvironments in these compartments influence tumor cell progression, yet this effect has not been investigated in an immunocompetent context. Here, we compared both mammary gland compartments as distinct inoculation sites, taking into account the immunological aspect by inoculating 4T1 tumor cells in immunocompetent mice. Following tumor cell inoculation in the adipose compartment of non-pretreated/naive, hormonally pretreated/naive and non-pretreated/lactating mice, the primary tumors developed similarly. However, a slower onset of primary tumor growth was found after inoculations in the luminal compartment of non-pretreated/lactating mice. Despite this difference in tumor development rate, metastasis to the liver and lungs was equally observed and was accompanied by lymphatic spreading of tumor cells and progressive splenomegaly with both inoculation types. Chitinase 3-like 1 (CHI3L1) and lipocalin 2 (LCN2) served as innovative biomarkers for disease progression showing increased levels in primary tumors and sera of the non-pretreated/lactating inoculation groups. A slower increase in circulating CHI3L1 but not LCN2 levels, was observed after inoculations in the luminal compartment which corroborated the slower tumor development at this inoculation site. Our results highlight the critical impact of different mammary gland compartments on tumor development in syngeneic murine models and support the use of novel tumor progression biomarkers in an immune-competent environment.

Increased Obesity-Associated Circulating Levels of the Extracellular Matrix Proteins Osteopontin, Chitinase-3 Like-1 and Tenascin C Are Associated with Colon Cancer.

BackgroundExcess adipose tissue represents a major risk factor for the development of colon cancer with inflammation and extracellular matrix (ECM) remodeling being proposed as plausible mechanisms. The aim of this study was to investigate whether obesity can influence circulating levels of inflammation-related extracellular matrix proteins in patients with colon cancer (CC), promoting a microenvironment favorable for tumor growth.MethodsSerum samples obtained from 79 subjects [26 lean (LN) and 53 obese (OB)] were used in the study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (44 without CC and 35 with CC). Anthropometric measurements as well as circulating metabolites and hormones were determined. Circulating concentrations of the ECM proteins osteopontin (OPN), chitinase-3-like protein 1 (YKL-40), tenascin C (TNC) and lipocalin-2 (LCN-2) were determined by ELISA.ResultsSignificant differences in circulating OPN, YKL-40 and TNC concentrations between the experimental groups were observed, being significantly increased due to obesity (P<0.01) and colon cancer (P<0.05). LCN-2 levels were affected by obesity (P<0.05), but no differences were detected regarding the presence or not of CC. A positive association (P<0.05) with different inflammatory markers was also detected.ConclusionsTo our knowledge, we herein show for the first time that obese patients with CC exhibit increased circulating levels of OPN, YKL-40 and TNC providing further evidence for the influence of obesity on CC development via ECM proteins, representing promising diagnostic biomarkers or target molecules for therapeutics.

Protein profiling of nasopharyngeal aspirates of hospitalized and outpatients revealed cytokines associated with severe influenza A(H1N1)pdm09 virus infections: A pilot study

Influenza A viruses (IAV) mutate rapidly and cause seasonal epidemics and occasional pandemics, which result in substantial number of patient visits to the doctors and even hospitalizations. We aimed here to identify inflammatory proteins, which levels correlated to clinical severity of the disease. For this we analysed 102 cytokines and growth factors in human nasopharyngeal aspirate (NPA) samples of 27 hospitalized and 27 outpatients diagnosed with influenza A(H1N1)pdm09 virus infection. We found that the relative levels of monocyte differentiation antigen CD14, lipocalin-2 (LCN2), C-C-motif chemokine 20 (CCL20), CD147, urokinase plasminogen activator surface receptor (uPAR), pro-epidermal growth factor (EGF), trefoil factor 3 (TFF3), and macrophage migration inhibitory factor (MIF) were significantly lower (p<0.008), whereas levels of retinol-binding protein 4 (RBP4), C-X-C motif chemokine 5 (CXCL5), interleukin-8 (IL-8), complement factor D (CFD), adiponectin, and chitinase-3-like 1 (CHI3L1) were significantly higher (p<0.008) in NPA samples of hospitalized than non-hospitalized patients. While changes in CD14, LCN2, CCL20, uPAR, EGF, MIF, CXCL5, IL-8, adiponectin and CHI3L1 levels have already been correlated with severity of IAV infection in mice and humans, our study is the first to describe association of CD147, RBP4, TFF3, and CFD with hospitalization of IAV-infected patients. Thus, we identified local innate immune profiles, which were associated with the clinical severity of influenza infections.

CHI3L1 polymorphisms, cord blood YKL-40 levels and later asthma development.

BackgroundSingle nucleotide polymorphisms (SNPs) in chitinase 3-like 1 (CHI3L1), the gene encoding YKL-40, and increased serum YKL-40 levels are associated with severe forms of asthma. It has never been addressed whether SNPs in CHI3L1 and cord blood YKL-40 levels could already serve as potential biomarkers for milder forms of asthma. We assessed in an unselected population whether SNPs in CHI3L1 and cord blood YKL-40 levels at birth are associated with respiratory symptoms, lung function changes, asthma, and atopy.MethodsIn a prospective birth cohort of healthy term-born neonates (n = 260), we studied CHI3L1 polymorphisms, and measured cord blood YKL-40 levels by ELISA in (n = 170) infants. Lung function was performed at 5 weeks and 6 years. Respiratory health during the first year of life was assessed weekly by telephone interviews. Diagnosis of asthma and allergic sensitisation was assessed at 6 years (n = 142).ResultsThe SNP rs10399805 was significantly associated with asthma at 6 years. The odds ratio for asthma was 4.5 (95 % CI 1.59–12.94) per T-allele. This finding was unchanged when adjusting for cord blood YKL-40 levels. There was no significant association for cord blood YKL-40 levels and asthma. SNPs in CHI3L1 and cord blood YKL-40 were not associated with lung function measurements at 5 weeks and 6 years, respiratory symptoms in the first year, and allergic sensitisation at 6 years.ConclusionGenetic variation in CHI3L1 might be related to the development of milder forms of asthma. Larger studies are warranted to establish the role of YKL-40 in that pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0239-8) contains supplementary material, which is available to authorized users.

Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1β and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia.

Pseudomonas aeruginosa causes hospital-acquired pneumonia and is associated with high mortality. An effective response to such an infection includes efficient clearance of pathogenic organisms while limiting collateral damage from the host inflammatory response, known as host resistance and host tolerance, respectively. P. aeruginosa expresses a type III secretion system (T3SS) needle complex that induces NLRC4 (NOD-like receptor C4) activation, interleukin-1β (IL-1β) production, and host tissue damage. Chitinase 3-like-1 (Chil1) is expressed during infection and binds to its receptor, IL-13 receptor α2 (IL-13Rα2), to regulate the pathogen-host response during Streptococcus pneumoniae infection, but the role Chil1 plays in balancing the host resistance and host tolerance during P. aeruginosa pneumonia is not known. We conducted experiments using C57BL/6 mice with or without a genetic deficiency of Chil1 and demonstrated that Chil1-deficient mice succumb to P. aeruginosa infection more rapidly than the wild type (WT). The decreased survival time in infected Chil1-deficient mice is associated with more neutrophils recruited to the airways, more lung parenchymal damage, and increased pulmonary consolidation while maintaining equivalent bacterial killing compared to WT mice. Infected Chil1-deficient mice and bone marrow-derived macrophages (BMDMs) from Chil1-deficient mice have increased production of tumor necrosis factor alpha (TNF-α) and IL-1β compared to infected WT mice and macrophages. Infection of Chil1-deficient BMDMs with non-NLRC4-triggering P. aeruginosa, which is deficient in the T3SS needle complex, did not alter the excessive IL-1β production compared to BMDMs from WT mice. The addition of recombinant Chil1 decreases the excessive IL-1β production but only partially rescues stimulated BMDMs from IL-13Rα2-deficient mice. Our data provide mechanistic insights into how Chil1 regulates P. aeruginosa-induced host responses.

Preliminary Study on Gene Expression of Chitinase-Like Cytokines in Human Airway Epithelial Cell Under Chitin and Chitosan Microparticles Treatment.

Small-sized chitin and chitosan microparticles (MPs) reduce allergic inflammation. We examined the capacity of these glycans to stimulate A549 human airway epithelial cells to determine the feasibility of using of these glycans as allergic therapeutic modality. A549 cells were treated with MPs and then expressions levels of chitinase domain-containing 1 (CHID1) and chitinase 3-like 1 (CHI3L1) genes were determined by quantitative real-time PCR. IL-6 production was measured by ELISA. Chitin MPs resulted in upregulation of CHI3L1 expression by 35.7-fold while mRNA expression did not change with chitosan MPs. Compared to the untreated group, production of IL-6 was significantly decreased in the chitosan MPs-treated group, but chitin MPs treatment cause elevation of IL-6 level. This study demonstrates that chitin potently induces CHI3L1 expression, but chitosan is relatively inert. This effect and inhibition of pro-inflammatory cytokine (IL-6) suggest that chitosan MPs may possess more potential for therapeutic uses in human airway allergic inflammation.

Tu1947 Serum Chitinase 3-like-1 (CHI3L1) and Fecal Calprotectin Levels for Non-Invasive Disease Activity Assessment in IBD Patients During Pregnancy

Tu1947 Serum Chitinase 3-like-1 (CHI3L1) and Fecal Calprotectin Levels for Non-Invasive Disease Activity Assessment in IBD Patients During Pregnancy

Tu1942 Fecal Chitinase 3-Like 1 Is a Reliable Marker As Accurate As Fecal Calprotectin in Detecting Endoscopic Activity in Adult Patients With Inflammatory Bowel Diseases

Tu1942 Fecal Chitinase 3-Like 1 Is a Reliable Marker As Accurate As Fecal Calprotectin in Detecting Endoscopic Activity in Adult Patients With Inflammatory Bowel Diseases