Chitinase 3 Like-1: An Emerging Molecule Involved in Diabetes and Diabetic Complications

Rosa, Michelino Di; Malaguarnera, Lucia

doi:10.1159/000444855

Cited by 49 publications

(34 citation statements)

References 138 publications

(187 reference statements)

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“…In line with these findings, both mRNA and protein expression levels of CHI3L1 were significantly increased in OVA‐sensitized WT mice compared to control WT mice. Numerous studies have shown elevated serum levels of YKL‐40 to be correlated with disease severity, and with poorer outcomes for many diseases, including cancer, psoriasis, rheumatoid arthritis, type 2 diabetes, liver fibrosis, atherosclerosis and coronary artery disease . CHI3L1 is considered a risk factor gene for allergic diseases and has polymorphisms which correlate with asthma prevalence and abnormal lung function .…”

Section: Discussionmentioning

confidence: 99%

“…to be correlated with disease severity, and with poorer outcomes for many diseases, including cancer, psoriasis, rheumatoid arthritis, type 2 diabetes, liver fibrosis, atherosclerosis and coronary artery disease. 9,13,33,34 CHI3L1 is considered a risk factor gene for allergic diseases and has polymorphisms which correlate with asthma prevalence and abnormal lung function. 35 pathway.…”

Section: Discussionmentioning

confidence: 99%

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

Kwak

Hong

Kim

et al. 2019

Clin Experimental Allergy

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Kwak

Hong

Kim

et al. 2019

Clin Experimental Allergy

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“…Chitinase 3-like-1 (Chi3L1), also called a breast regression protein 39 (BRP-39) in mouse and YKL-40 in human, is known as a secreted glycoprotein and prototypic mammalian chitinase like protein [11,12]. Increased expression of Chi3L1 protein and mRNA have been shown in various disease models and states including rheumatoid arthritis schizophrenics, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma, diabetes, and atherosclerosis [13][14][15][16][17][18][19], Especially, Chi3L1 expression has been found in a variety of cancer cells such as breast, lung, prostate, colon, rectum, ovary, kidney, breast, glioblastomas, and malignant melanoma [20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis

et al. 2020

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Background: Chitinase 3 like 1 protein (Chi3L1) is expressed in several cancers, and a few evidences suggest that the secreted Chi3L1 contributes to tumor development. However, the molecular mechanisms of intracellular Chi3L1 are unknown in the lung tumor development. Methods: In the present study, we generated Chi3L1 knockout mice (Chi3L1 KO(−/−) ) using CRISPR/Cas9 system to investigate the role of Chi3L1 on lung tumorigenesis. Results:We established lung metastasis induced by i.v. injections of B16F10 in Chi3L1 KO(−/−) . The lung tumor nodules were significantly reduced in Chi3L1 KO(−/−) and protein levels of p53, p21, BAX, and cleaved-caspase 3 were significantly increased in Chi3L1 KO(−/−) , while protein levels of cyclin E1, CDK2, and phsphorylation of STAT3 were decreased in Chi3L1 KO(−/−) . Allograft mice inoculated with B16F10 also suppressed tumor growth and increased p53 and its target proteins including p21 and BAX. In addition, knockdown of Chi3L1 in lung cancer cells inhibited lung cancer cell growth and upregulated p53 expression with p21 and BAX, and a decrease in phosphorylation of STAT3. Furthermore, we found that intracellular Chi3L1 physically interacted and colocalized with p53 to inhibit its protein stability and transcriptional activity for target genes related with cell cycle arrest and apoptosis. In lung tumor patient, we clinically found that Chi3L1 expression was upregulated with a decrease in p53 expression, as well as we validated that intracellular Chi3L1 was colocalized, reversely expressed, and physically interacted with p53, which results in suppression of the expression and function of p53 in lung tumor patient.Conclusions: Our studies suggest that intracellular Chi3L1 plays a critical role in the lung tumorigenesis by regulating its novel target protein, p53 in both an in vitro and in vivo system.

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“…It is known that pro-in ammatory cytokines such as IFN-γ, TNF-α, IL-1β, and IL-6 are involved in the expression of CHI3L1 [20]. The excessive increase in CHI3L1 can have unpredictable pathological effects by initiating and persisting chronic in ammation [21]. Several clinical studies reported that the elevation of CHI3L1 was observed in patients suffering from a wide range of diseases: cancer, metabolic, and neurological diseases [22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

Ham

Lee

Yun

et al. 2020

Preprint

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Background Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. We have previously demonstrated that the 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), the inhibitor of CHI3L1, has an inhibitory effect on memory impairment in Αβ infusion mouse model and on LPS-induced neuroinflammation in the murine BV-2 microglia and primary cultured astrocyte. Methods In the present study, we investigated that the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and more detailed correlation of CHI3L1 and AD. To investigate the effects of K284-6111 on memory dysfunction, we administered K284-6111 (3 mg/kg, p.o.) daily for four weeks to Tg2576, followed by behavioral tests of water maze test, probe test, and passive avoidance test.Results Administration of K284-6111 alleviated memory impairment in Tg2576 mice and had the effect of reducing accumulation of Aβ and neuroinflammatory responses in the mouse brain. K284-6111 treatment also selectively inactivated ERK and NF-κB pathways, which were activated when CHI3L1 was overexpressed, in mouse brain and in BV-2 cells. Web-based gene network analysis and our results of gene expression level in BV-2 cells showed that CHI3L1 is closely correlated with PTX3. Our result revealed that knockdown of PTX3 has inhibitory effect on the production of inflammatory proteins and cytokines, and on the phosphorylation of ERK and IκBα.Conclusion These results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 through blocking ERK dependent PTX3 pathway.

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Chitinase 3 Like-1: An Emerging Molecule Involved in Diabetes and Diabetic Complications

Cited by 49 publications

References 138 publications

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

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

Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

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