TNF-α induces autophagy through ERK1/2 pathway to regulate apoptosis in neonatal necrotizing enterocolitis model cells IEC-6

Yuan, Yongjie; Ding, Daokui; Zhang, Ning; Xia, Ziqiang; Wang, Jiaxiang; Yang, Heying; Guo, Fei; Li, Bing

doi:10.1080/15384101.2018.1482150

Cited by 61 publications

(52 citation statements)

References 40 publications

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“…As autophagic and apoptotic programs appear to inhibit each other (42), and apoptosis participates in the DC life cycle and elimination after maturation (8), we investigated if Dab2 deletion could impact DC apoptosis. To test that, DC2.4 WT and DC2.4 Dab2 − / − DCs were treated with staurosporine, an apoptosis inducer, for up to 3 h and apoptosis was detected by 7AAD/Annexin V labeling and flow cytometry and by Western blot analysis of the cleaved caspase-3 (17 kDa) expression.…”

Section: Resultsmentioning

confidence: 99%

Rapid Downregulation of DAB2 by Toll-Like Receptor Activation Contributes to a Pro-Inflammatory Switch in Activated Dendritic Cells

et al. 2019

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Dendritic cells (DCs) are pivotal in regulating tolerogenic as well as immunogenic responses against microorganisms by directing both the innate and adaptive immune response. In health, phenotypically different DC subsets found in the gut mucosa are maintained in their tolerogenic state but switch to a pro-inflammatory phenotype during infection or chronic autoinflammatory conditions such as inflammatory bowel disease (IBD). The mechanisms that promote the switch among the mucosal DCs from a tolerogenic to an immunogenic, pro-inflammatory phenotype are incompletely understood. We hypothesized that disabled homolog 2 (DAB2), recently described as a negative regulator of DC immunogenicity during their development, is regulated during intestinal inflammation and modulates mucosal DC function. We show that DAB2 is highly expressed in colonic CD11b + CD103 − DCs, a subset known for its capacity to induce inflammatory Th1/Th17 responses in the colon, and is downregulated predominantly in this DC subset during adoptive T cell transfer colitis. Administration of Dab2-deficient DCs (DC2.4 Dab2 − / − cells) modulated the course of DSS colitis in wild-type mice, enhanced mucosal expression of Tnfa, Il6 , and Il17a , and promoted neutrophil recruitment. In bone-marrow derived dendritic cells (BMDC), DAB2 expression correlated with CD11b levels and DAB2 was rapidly and profoundly inhibited by TLR ligands in a TRIF- and MyD88-dependent manner. The negative modulation of DAB2 was biphasic, initiated with a quick drop in DAB2 protein, followed by a sustained reduction in Dab2 mRNA. DAB2 downregulation promoted a more functional and activated DC phenotype, reduced phagocytosis, and increased CD40 expression after TLR activation. Furthermore, Dab2 knockout in DCs inhibited autophagy and promoted apoptotic cell death. Collectively, our results highlight the immunoregulatory role for DAB2 in the intestinal dendritic cells and suggest that DAB2 downregulation after microbial exposure promotes their switch to an inflammatory phenotype.

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Section: Resultsmentioning

confidence: 99%

Rapid Downregulation of DAB2 by Toll-Like Receptor Activation Contributes to a Pro-Inflammatory Switch in Activated Dendritic Cells

et al. 2019

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“…In the present study, we showed that TNF‐α‐induced autophagy also contributes to a decrease in BMPR2 levels. One of the presumed mechanisms on how inflammation induces autophagy might be through ERK1/2 MAP kinase pathway activation . In addition, TNF‐α has also been shown to upregulate the expression of the autophagy genes LC3 and beclin 1 through Jun kinase signalling pathway activation and AKT/PKB inhibition .…”

Section: Discussionmentioning

confidence: 99%

Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension

Gomez‐Puerto

Zuijen

Huang

et al. 2019

The Journal of Pathology

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Pulmonary arterial hypertension (PAH) is characterised by an increase in mean pulmonary arterial pressure which almost invariably leads to right heart failure and premature death. More than 70% of familial PAH and 20% of idiopathic PAH patients carry heterozygous mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2). However, the incomplete penetrance of BMPR2 mutations suggests that other genetic and environmental factors contribute to the disease. In the current study, we investigate the contribution of autophagy in the degradation of BMPR2 in pulmonary vascular cells. We demonstrate that endogenous BMPR2 is degraded through the lysosome in primary human pulmonary artery endothelial (PAECs) and smooth muscle cells (PASMCs): two cell types that play a key role in the pathology of the disease. By means of an elegant HaloTag system, we show that a block in lysosomal degradation leads to increased levels of BMPR2 at the plasma membrane. In addition, pharmacological or genetic manipulations of autophagy allow us to conclude that autophagy activation contributes to BMPR2 degradation. It has to be further investigated whether the role of autophagy in the degradation of BMPR2 is direct or through the modulation of the endocytic pathway. Interestingly, using an iPSC‐derived endothelial cell model, our findings indicate that BMPR2 heterozygosity alone is sufficient to cause an increased autophagic flux. Besides BMPR2 heterozygosity, pro‐inflammatory cytokines also contribute to an augmented autophagy in lung vascular cells. Furthermore, we demonstrate an increase in microtubule‐associated protein 1 light chain 3 beta (MAP1LC3B) levels in lung sections from PAH induced in rats. Accordingly, pulmonary microvascular endothelial cells (MVECs) from end‐stage idiopathic PAH patients present an elevated autophagic flux. Our findings support a model in which an increased autophagic flux in PAH patients contributes to a greater decrease in BMPR2 levels. Altogether, this study sheds light on the basic mechanisms of BMPR2 degradation and highlights a crucial role for autophagy in PAH. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Intraperitoneal injection of chloroquine, an autophagy inhibitor, attenuates excessive inflammatory response in DSS-treated erbin -/mice [18]. Using in vitro and in vivo models of neonatal necrotizing enterocolitis, an inflammatory intestinal disease of new-born infants, it was reported that TNF induces autophagy via the MAPK1/ERK2 (mitogen-activated protein kinase 1)-MAPK3/ERK1 pathway to suppress cell proliferation and promote apoptosis, which might consequently favor disease development [19]. Even if these studies diverged in the precise mechanism of cell death, they all suggested that defective autophagy may lead to an excessive level of epithelial cell death, favoring IBD development.…”

Section: Autophagy and Epithelial Cell Deathmentioning

confidence: 99%

New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD

2019

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One of the most significant challenges of inflammatory bowel disease (IBD) research is to understand how alterations in the symbiotic relationship between the genetic composition of the host and the intestinal microbiota, under impact of specific environmental factors, lead to chronic intestinal inflammation. Genome-wide association studies, followed by functional studies, have identified a role for numerous autophagy genes in IBD, especially in Crohn disease. Studies using in vitro and in vivo models, in addition to human clinical studies have revealed that autophagy is pivotal for intestinal homeostasis maintenance, gut ecology regulation, appropriate intestinal immune responses and anti-microbial protection. This review describes the latest researches on the mechanisms by which dysfunctional autophagy leads to disrupted intestinal epithelial function, gut dysbiosis, defect in anti-microbial peptide secretion by Paneth cells, endoplasmic reticulum stress response and aberrant immune responses to pathogenic bacteria. A better understanding of the role of autophagy in IBD pathogenesis may provide better sub-classification of IBD phenotypes and novel approaches for disease management.

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TNF-α induces autophagy through ERK1/2 pathway to regulate apoptosis in neonatal necrotizing enterocolitis model cells IEC-6

Cited by 61 publications

References 40 publications

Rapid Downregulation of DAB2 by Toll-Like Receptor Activation Contributes to a Pro-Inflammatory Switch in Activated Dendritic Cells

Rapid Downregulation of DAB2 by Toll-Like Receptor Activation Contributes to a Pro-Inflammatory Switch in Activated Dendritic Cells

Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension

New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD

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