Chitinase-3-Like-1 Promotes M2 Macrophage Differentiation and Induces Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration

Xu, Nana; Bo, Qiyu; Shao, Rong; Liang, Jian; Zhai, Yadi; Yang, Sheng; Wang, Fenghua; Sun, Xiaodong

doi:10.1167/iovs.19-27493

Cited by 61 publications

(65 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other studies have reported that CHI3L1 contributes to polarization to M2 macrophage [48][49][50], but in our results, K284-6111-administrated Tg2576 mouse showed lower mRNA level of Tnf, Il1b, Il6, and Cd86. Moreover, overexpression of CHI3L1 increased the expression of markers of M1 microglia, Tnf, Il1b, Il6, and Cd86, and inhibited by K284-6111 treatment.…”

Section: Discussioncontrasting

confidence: 94%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

confidence: 94%

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

View full text Add to dashboard Cite

show abstract

“…Consistent with our previous findings, the present study showed that overexpression of CHI3L1 increased expression of pro-inflammatory cytokines, Cd86 , one of the markers of M1 microglia, and inflammatory proteins in CHI3L1 overexpressing BV-2 cells. Other studies have reported that CHI3L1 contributes to polarization to M2 macrophage [ 50 – 52 ], but in our results, K284-6111-administrated Tg2576 mouse showed lower mRNA level of Tnf, Il1b, Il6, and Cd86 . Moreover, overexpression of CHI3L1 increased the expression of markers of M1 microglia, Tnf, Il1b, Il6, and Cd86 , and inhibited by K284-6111 treatment.…”

Section: Discussioncontrasting

confidence: 91%

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

J Neuroinflammation

View full text Add to dashboard Cite

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-cyclohexene-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 the 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 the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and a 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 4 weeks to Tg2576 mice, 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 the 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 the 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 an 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 enhancing ERK-dependent PTX3 pathway.

show abstract

“… 143 Upon recruitment and activation, CHI3L1 induces M2 macrophage (alternatively activated) differentiation by the phosphorylation of Erk. 19 , 148 Conversely, CHI3L1 is highly expressed in S. aureus -stimulated macrophages, where it promotes M1 polarization of macrophages (classically activated) via activation of the MAPK pathway. 149 Mechanistically, CHI3L1 secreted from M2 macrophages interacts with IL-13Rα2 on the plasma membrane of cancer cells, triggering the activation of the MAPK signaling pathway in GC and breast cancer.…”

Section: Chi3l1 In Oncogenesismentioning

confidence: 99%

“…CHI3L1 plays a crucial role in protecting against pathogens, antigen-induced and oxidant-induced injury responses, inflammation, and tissue repair and remodeling by regulating a variety of essential biological processes including oxidant injury, apoptosis, pyroptosis, inflammasome activation, Th1/Th2 inflammatory balance, M2 macrophage differentiation, dendritic cell (DC) accumulation, TGF-β1 expression, ECM regulation, and parenchymal scarring. 16 – 19 …”

Section: Introductionmentioning

confidence: 99%

Chitinase-3 like-protein-1 function and its role in diseases

Zhao

et al. 2020

Sig Transduct Target Ther

325

265

View full text Add to dashboard Cite

Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4+ T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.

show abstract

Chitinase-3-Like-1 Promotes M2 Macrophage Differentiation and Induces Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration

Abstract: Chitinase-3-like-1 promotes M2 macrophage differentiation and induces choroidal neovascularization in neovascular age-related macular degeneration.

Cited by 61 publications

References 46 publications

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

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

K284-6111 alleviates memory impairment and neuroinflammation in Tg2576 mice by inhibition of Chitinase-3-like 1 regulating ERK-dependent PTX3 pathway

Chitinase-3 like-protein-1 function and its role in diseases

Contact Info

Product

Resources

About