Regulation of chitinase-3-like-1 in T cell elicits Th1 and cytotoxic responses to inhibit lung metastasis

Kim, Do Hyun; Park, Hong Jai; Lim, Su-Ho; Koo, Ja Hyun; Lee, Hong-Gyun; Choi, Jin Ouk; Oh, Ji Hoon; Ha, Sang Jun; Kang, Min Jong; Lee, Chang Min; Lee, Chang-Min; Elias, Jack A.; Choi, Je-Min

doi:10.1038/s41467-017-02731-6

Cited by 86 publications

(82 citation statements)

References 55 publications

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“…In our murine model of AD induced by OVA, CHI3L1 deficiency resulted in the attenuation of allergic skin inflammation and was accompanied by low Th2 cytokine levels and effector CD4 + T cell populations, suggesting that CHI3L1 promotes Th2 immune responses. Consistent with this finding, a recent study demonstrated that BRP‐39 −/− CD4 + T cells are prone to Th1 differentiation, and that they show reduced Th2 differentiation via an IFNγ signalling pathway . Additionally, in the absence of CHI3L1, IL‐18‐induced pulmonary inflammatory responses were significantly ameliorated by downregulation of Th2 and Th17 responses …”

Section: Discussionsupporting

confidence: 61%

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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: Discussionsupporting

confidence: 61%

“…35 pathway. 36 Additionally, in the absence of CHI3L1, IL-18-induced pulmonary inflammatory responses were significantly ameliorated by downregulation of Th2 and Th17 responses. 37,38 CHI3L1 is widely recognized as an important regulator of both M2 macrophage activation and Th2 inflammation.…”

Section: Discussionmentioning

confidence: 97%

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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“…Rather, they appear to have evolved to play a role in the development and progression of Th2 immune responses and in defence against parasitic infections and cancer (54)(55)(56). Chitinase-like proteins are expressed by macrophages and T cells and are involved in lung inflammation, remodelling and fibrosis (35,36) and CHIT1 and CHI3L1 have previously been shown to be induced in alveolar macrophages during mycobacterial infection (30). Other genes upregulated in discarded lungs included SLC7A5 and GBP5.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, serum CHIT1 has been investigated as a biomarker of disease severity and progression in several lung diseases, including chronic obstructive pulmonary disease (34). Chitinase-like proteins (including CHI3L1) are expressed by alveolar macrophages and play a role in lung inflammation, remodeling and fibrosis (35,36). Of note, SLC7A5 (an amino acid transporter) and GBP5 (Guanylate-binding protein 5) promote NLRP3 inflammasome activation and IL1ß production in monocytes and macrophages (37,38).…”

Section: Lungs Deemed Unusable Have Increased Induction Of Immune Patmentioning

confidence: 99%

Transcriptional analysis identifies novel biomarkers associated with successful ex-vivo perfusion of human donor lungs

Ferdinand

Andreasson

et al. 2019

Preprint

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Transplantation is an effective treatment for end-stage lung disease but donor organ shortage is a major problem. Ex-vivo lung perfusion (EVLP) of marginal organs enables functional assessment under normothermic conditions to facilitate clinical decision-making around utilisation, but the molecular processes occurring during EVLP, and how they differ between more or less viable lungs, remains to be determined. Here we used RNA sequencing to delineate changes in gene expression occurring in n=10 donor lungs undergoing EVLP, comparing lungs that were deemed transplantable (n=6) to those deemed unusable (n=4). We found that lungs deemed suitable for transplantation following EVLP had reduced induction of a number of innate immune pathways during EVLP, but a greater increase in genes involved in oxidative phosphorylation, a critical ATP-degenerating pathway. Furthermore, SCGB1A1, a gene encoding an anti-inflammatory secretoglobin CC10, and other club cell genes were significantly increased in transplantable lungs following perfusion, whilst CHIT-1 was decreased.Using a larger validation cohort (n=18), we confirmed that the ratio of CHIT1 and SCGB1A1 protein levels in lung perfusate have potential utility to distinguish transplantable and nontransplantable lungs (AUC 0.81). Together, our data identify novel biomarkers that may assist with pre-transplant lung assessment, as well as pathways that may amenable to therapeutic intervention during EVLP. Single sentence summaryTranscriptional changes in lungs undergoing ex vivo normothermic perfusion identify chitinase1 and club cell genes as potential biomarkers to guide utilisation

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Regulation of chitinase-3-like-1 in T cell elicits Th1 and cytotoxic responses to inhibit lung metastasis

Cited by 86 publications

References 55 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

Transcriptional analysis identifies novel biomarkers associated with successful ex-vivo perfusion of human donor lungs

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