Dataset Information

The Modulation of Regulatory T Cells via HMGB1/PTEN/?-Catenin Axis in LPS Induced Acute Lung Injury.

ABSTRACT: Sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains the leading complication for mortality caused by bacterial infection. The regulatory T (Treg) cells appear to be an important modulator in resolving lung injury. Despite the extensive studies, little is known about the role of macrophage HMGB1/PTEN/?-catenin signaling in Treg development during ALI. Objectives: This study was designed to determine the roles and molecular mechanisms of HMGB1/PTEN/?-catenin signaling in mediating CD4⁺CD25⁺Foxp3⁺ Treg development in sepsis-induced lung injury in mice. Setting: University laboratory research of First Affiliated Hospital of Anhui Medical University. Subjects: PTEN/?-catenin Loxp and myeloid-specific knockout mice. Interventions: Groups of PTEN^loxp/?-catenin^loxp and myeloid-specific PTEN/?-catenin knockout (PTEN^M-KO/?-catenin^M-KO) mice were treated with LPS or recombinant HMGB1 (rHMGB1) to induce ALI. The effects of HMGB1-PTEN axis were further analyzed by in vitro co-cultures. Measures and Main Results: In a mouse model of ALI, blocking HMGB1 or myeloid-specific PTEN knockout (PTEN^M-KO) increased animal survival/body weight, reduced lung damage, increased TGF-? production, inhibited the expression of ROR?t and IL-17, while promoting ?-catenin signaling and increasing CD4⁺CD25⁺Foxp3⁺ Tregs in LPS- or rHMGB-induced lung injury. Notably, myeloid-specific ?-catenin ablation (?-catenin^M-KO) resulted in reduced animal survival and increased lung injury, accompanied by reduced CD4⁺CD25⁺Foxp3⁺ Tregs in rHMGB-induced ALI. Furthermore, disruption of macrophage HMGB1/PTEN or activation of ?-catenin significantly increased CD4⁺CD25⁺Foxp3⁺ Tregs in vitro. Conclusions: HMGB1/PTEN/?-catenin signaling is a novel pathway that regulates Treg development and provides a potential therapeutic target in sepsis-induced lung injury.

SUBMITTER: Zhou M

PROVIDER: S-EPMC6669370 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Modulation of Regulatory T Cells via HMGB1/PTEN/β-Catenin Axis in LPS Induced Acute Lung Injury.

Zhou Min M Fang Haoshu H Du Min M Li Changyong C Tang Rui R Liu Haiyan H Gao Zhi Z Ji Zongshu Z Ke Bibo B Chen Xu-Lin XL

Frontiers in immunology 20190725

Sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains the leading complication for mortality caused by bacterial infection. The regulatory T (Treg) cells appear to be an important modulator in resolving lung injury. Despite the extensive studies, little is known about the role of macrophage HMGB1/PTEN/β-catenin signaling in Treg development during ALI. <b>Objectives:</b> This study was designed to determine the roles and molecular mechanisms of HMGB1/PTEN/β-ca ...[more]

PMID: 31402909

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Project description:BackgroundAccumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are involved in the hypoxia-related cancer process and play pivotal roles in enabling malignant cells to survive under hypoxic stress. However, the molecular crosstalk between lncRNAs and hypoxia signaling cascades in non-small cell lung cancer (NSCLC) remains largely elusive.MethodsFirstly, we identified differentially expressed lncRNA cancer susceptibility candidate 15 (CASC15) as associated with NSCLC based on bioinformatic data. The clinical significance of CASC15 in lung cancer was investigated by Kaplan-Meier survival analysis. Then, we modulated CASC15 expression in NSCLC cell lines by RNAi. CCK-8 and transwell assays were carried out to examine the effects of CASC15 on proliferation and migration of NSCLC cells. Upstream activator and downstream targets of CASC15 were validated by luciferase reporter assay, qRT-PCR, Western blotting, and chromatin immunoprecipitation (ChIP). Lastly, RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC) were performed to confirm the genetic relationships between CASC15 and related genes in clinical samples.ResultsCASC15 was highly expressed in NSCLC tissues and closely associated with poor prognosis. Loss-of-function analysis demonstrated that CASC15 was essential for NSCLC cell migration and growth. Mechanistic study revealed that CASC15 was transcriptionally activated by hypoxia signaling in NSCLC cells. Further analysis showed that hypoxia-induced CASC15 transactivation was mainly dependent on hypoxia-inducible factor 1α (HIF-1α) and hypoxia response elements (HREs) located in CASC15 promoter. CASC15 promotes the expression of its chromosomally nearby gene, SOX4. Then SOX4 functions to stabilize β-catenin protein, thereby enhancing the proliferation and migration of NSCLC cells. HIF-1α/CASC15/SOX4/β-catenin pathway was activated in a substantial subset of NSCLC patients.ConclusionsHIF-1α/CASC15/SOX4/β-catenin axis plays an essential role in the development and progression of NSCLC. The present work provides new evidence that lncRNA CASC15 holds great promise to be used as novel biomarkers for NSCLC. Blocking the HIF-1α/CASC15/SOX4/β-catenin axis can serve as a potential therapeutic strategy for treating NSCLC.

Dataset Information

The Modulation of Regulatory T Cells via HMGB1/PTEN/?-Catenin Axis in LPS Induced Acute Lung Injury.

Publications

The Modulation of Regulatory T Cells via HMGB1/PTEN/β-Catenin Axis in LPS Induced Acute Lung Injury.

Similar Datasets

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