Deletion of Chitinase-3-like 1 accelerates stroke development through enhancement of Neuroinflammation by STAT6-dependent M2 microglial inactivation in Chitinase-3-like 1 knockout mice

Im, Jun Hyung; Yeo, In Jun; Park, Pil Hoon; Choi, Dong Young; Han, Sang‐Bae; Yun, Jaesuk; Hong, Jin Tae

doi:10.1016/j.expneurol.2019.113082

Cited by 42 publications

(38 citation statements)

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“…Therefore, we hypothesised that the suppression of STAT phosphorylation might be the consequence of CHI3L1-induced PPARδ expression. Previous studies showed that CHI3L1 induced Wnt/ β-catenin, Erk1/2, Akt signaling and STAT6 activation 6,11,43,[47][48][49] , and all of these pathways were evidenced to be able to induce PPARδ expression in different cell contexts [50][51][52][53] . We found that MSC-derived CHI3L1 indeed promoted PPARδ expression and decreased the phosphorylation of STAT1/3 in T cells and the PPARδ agonist could inhibit the function of T cells.…”

Section: Discussionmentioning

confidence: 96%

“…Elevated CHI3L1 expression plays a major role in microenvironment remodelling in different diseases 10 . Recent studies revealed that CHI3L1 had an immunosuppressive function, such as, CHI3L1 negatively regulates T cell activation, and deficiency of CHI3L1 accelerates stroke development through enhancement of neuroinflammation via decreasing M2 macrophage polarisation [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression

Liu

Pan

et al. 2021

Cell Death Dis

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Liver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression

Liu

Pan

et al. 2021

Cell Death Dis

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“… 27 By contrast, in another pre-clinical animal model, Chi3L1 knockout deteriorated ischemia/reperfusion damage. 28 It is unclear whether the management of serum YKL-40 levels within the appropriate range is beneficial or harmful in AIS, which deserved to be further investigated in the future.…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between Serum YKL-40 Levels on Admission and Stroke-Associated Pneumonia in Patients with Acute Ischemic Stroke

Shi

Chen

Gong

et al. 2021

JIR

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Background Stroke-associated pneumonia (SAP) is a standout complication after acute ischemic stroke (AIS), with a prevalence of 7–38%. The aim of this prospective study was to investigate the relationship between serum YKL-40 levels at admission and SAP. Methods Between August 2020 and February 2021, consecutive AIS patients from two centers were enrolled prospectively. Serum YKL-40 concentrations were measured via enzyme-linked immunosorbent assay. We performed logistic regression analyses to explore the relationship between YKL-40 and SAP. Receiver operating characteristic curve was also used to assess the predictive ability of YKL-40 in predicting SAP. Results Ultimately, a total of 511 AIS patients were recruited. Multivariate logistic regression analysis showed that YKL-40 was independently related to SAP, whether as a continuous variable or as quartiles ( P =0.001). The area under curve of YKL-40 to predict SAP was 0.765. The optimal cutoff value of YKL-40 as a predictor of SAP was determined to be 206.4 ng/mL, where the sensitivity was 63.1% and the specificity was 82.0%. Conclusion Our study demonstrated that YKL-40 might be considered as a useful biomarker to predict SAP in AIS patients.

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“…A large number of significant DEGs identified by our CVD model ( Supplementary Table 1 ) were associated with inflammation. For instance, the most significantly upregulated gene in the spinal cord, CHI3L1 , is related to a variety of inflammatory disorders ( Kastrup et al, 2009 ; Johansen et al, 2010 ; Im et al, 2020 ) and coronary artery disease ( Rathcke and Vestergaard, 2009 ). Gene FCGR3A —upregulated in three of the CVD tissues (Brain – Spinal cord adj.P.val = 0.02; Brain – Caudate adj.P.val = 0.03; Artery – Tibial adj.P.val = 0.02)—encodes a receptor that binds the Fc portion of IgG, and it affects the pharmacokinetics in patients with Crohn’s Disease ( Termant et al, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

Exploring the Impact of Cerebrovascular Disease and Major Depression on Non-diseased Human Tissue Transcriptomes

Poon

Chen

2021

Front. Genet.

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BackgroundThe development of complex diseases is contributed by the combination of multiple factors and complicated interactions between them. Inflammation has recently been associated with many complex diseases and may cause long-term damage to the human body. In this study, we examined whether two types of complex disease, cerebrovascular disease (CVD) or major depression (MD), systematically altered the transcriptomes of non-diseased human tissues and whether inflammation is linked to identifiable molecular signatures, using post-mortem samples from the Genotype-Tissue Expression (GTEx) project.ResultsFollowing a series of differential expression analyses, dozens to hundreds of differentially expressed genes (DEGs) were identified in multiple tissues between subjects with and without a history of CVD or MD. DEGs from these disease-associated tissues—the visceral adipose, tibial artery, caudate, and spinal cord for CVD; and the hypothalamus, putamen, and spinal cord for MD—were further analyzed for functional enrichment. Many pathways associated with immunological events were enriched in the upregulated DEGs of the CVD-associated tissues, as were the neurological and metabolic pathways in DEGs of the MD-associated tissues. Eight gene-tissue pairs were found to overlap with those prioritized by our transcriptome-wide association studies, indicating a potential genetic effect on gene expression for circulating cytokine phenotypes.ConclusionCerebrovascular disease and major depression cause detectable changes in the gene expression of non-diseased tissues, suggesting that a possible long-term impact of diseases, lifestyles and environmental factors may together contribute to the appearance of “transcriptomic scars” on the human body. Furthermore, inflammation is probably one of the systemic and long-lasting effects of cerebrovascular events.

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Deletion of Chitinase-3-like 1 accelerates stroke development through enhancement of Neuroinflammation by STAT6-dependent M2 microglial inactivation in Chitinase-3-like 1 knockout mice

Cited by 42 publications

References 58 publications

Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression

Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression

The Relationship Between Serum YKL-40 Levels on Admission and Stroke-Associated Pneumonia in Patients with Acute Ischemic Stroke

Exploring the Impact of Cerebrovascular Disease and Major Depression on Non-diseased Human Tissue Transcriptomes

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