Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis

Lambelet, Martine; Terra, Letícia Ferreira; Fukaya, Makiko; Meyerovich, Kira; Labriola, Letícia; Cardozo, Alessandra K; Allagnat, Florent

doi:10.1038/s41419-017-0121-5

Cited by 68 publications

(73 citation statements)

References 54 publications

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“…Furthermore, autophagy and crinophagy are dynamic processes, and our analyses represent only a static snapshot in time. It is clear that exogenous factors may dynamically change autophagic flux associated with lysosome dysfunction in the beta cell, as is the case for our data and evidence in the literature of the effects elicited by proinflammatory cytokines [43]. Therefore, while our data suggest globally impaired autophagy and crinophagy in human type 1 diabetes, perhaps linked to defective lysosome function, they are only suggestive and do not tell us if the kinetics are perturbed during diabetes pathogenesis.…”

Section: Discussionmentioning

confidence: 50%

Pancreatic Beta Cell Autophagy is Impaired in Type 1 Diabetes

Muralidharan

Conteh

Marasco

et al. 2020

Preprint

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Aims/hypothesisPancreatic beta cells are highly metabolic secretory cells that are subjected to exogenous damaging factors such as proinflammatory cytokines or excess glucose that can cause accumulation of damage-inducing reactive oxygen species (ROS) during the pathogenesis of diabetes. We and others have shown that beta cell autophagy can reduce ROS to protect against apoptosis both in vitro and in vivo. While impaired islet autophagy has been demonstrated in human type 2 diabetes, it is unknown if islet autophagy is perturbed in the pathogenesis of type 1 diabetes. We hypothesized that beta cell autophagy is dysfunctional in type 1 diabetes, and that there is a progressive loss during early diabetes development.MethodsMouse pancreata were collected from chloroquine injected and non-injected NOR, nondiabetic NOD, and diabetic NOD mice. Age and BMI-matched pancreas tissue sections from human organ donors (n=34) were obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD). To assess autophagic flux, we injected the mice with chloroquine to inhibit the final stages of autophagy. We analyzed tissues for markers of autophagy via immunofluorescence analysis. Tissue sections were stained with antibodies against proinsulin or insulin (beta cell markers), LC3A/B (autophagosome marker), Lamp1 (lysosome marker), and p62 (autophagy adaptor protein and marker for autophagic flux). Images were collected on a scanning laser confocal microscope then analyzed with CellProfiler and ImageJ. Secondary lysosomes and telolysosomes (formerly called lipofuscin bodies, residual bodies or tertiary lysosomes) were analyzed in electron micrographs of pancreatic tissue sections from human organ donors (nPOD; n=12) deposited in www.nanotomy.org/OA/nPOD. Energy Dispersive X-ray (EDX) analysis was also performed on these tissues to analyze distribution of elements such as nitrogen, phosphorus, and osmium in secondary lysosomes and telolysosomes of nondiabetic and autoantibody positive donor tissues (n=5).ResultsWe observed increased autophagosome numbers in islets of diabetic NOD mice (p=0.0077) and increased p62 in islets of both nondiabetic and diabetic NOD mice (p<0.0001 in both cases) when compared to NOR mice. There was also a significant reduction in autophagosome:lysosome colocalization in islets of diabetic NOD mice compared to both nondiabetic NOD mice (p=0.0004) and NOR mice (p=0.0003). Chloroquine infusions elicited accumulation of autophagosomes in the islets of NOR (p=0.0029) and nondiabetic NOD mice (p<0.0001), but not in the islets of diabetic NOD mice. Chloroquine also stimulated an accumulation of the autophagy adaptor protein p62 in the islets of NOR mice (p<0.001), however this was not observed in NOD mice (regardless of diabetes status). In the human pancreata, we observed significantly reduced autophagosome:lysosome colocalization (p=0.0002) in the residual beta cells of donors with type 1 diabetes compared to nondiabetic controls. We also observed reduced colocalization of proinsulin with lysosomes in the residual beta cells of donors with type 1 diabetes compared to both nondiabetic (p<0.0001) and autoantibody positive donors (p<0.0001). Electron microscopy based analysis of human pancreas sections also revealed accumulation of telolysosomes in beta cells of autoantibody positive donors (p=0.0084), the majority of which had an nitrogen dense ring outside a phospholipid core.Conclusions/interpretationCollectively, we provide evidence of impairment in the final degradation stages of islet macroautophagy and crinophagy in human type 1 diabetes. We also document an accumulation of telolysosomes with nitrogen accumulation at their periphery in the beta cells of autoantibody positive donors. This demonstrates clear differences in the lysosome contents of autoantibody positive donors that may be associated with lysosome dysfunction prior to clinical hyperglycemia. We observe similar impairments in macroautophagy in the diabetic NOD mouse, a model of type 1 diabetes, suggesting that this mouse model can be appropriately used to study the pathogenesis of autophagy/crinophagy loss and how it relates to disease initiation and progression. Considering these data in the context of what is known regarding the cell-protective effects of islet autophagy, we suggest targeting beta cell autophagy pathways as an approach to reduce apoptosis in individuals at risk for type 1 diabetes development.Research in contextWhat is already known about this subject?Autophagy confers a cytoprotective role in the beta cell.Autophagy is reduced in type 2 diabetes.Autophagy in the context of type 1 diabetes is unexplored.What is the key question?Is autophagy reduced during the pathogenesis of human type 1 diabetes?What are the new findings?We provide evidence of reduced autophagy and crinophagy in human type 1 diabetes.These data are supported by observations of reduced autophagy in a mouse model of autoimmune diabetes.How might this impact on clinical practice in the foreseeable future?This study provides evidence that autophagy is impaired in human type 1 diabetes. Prior studies have shown that loss of autophagy in the islet is associated with increased beta cell apoptosis, therefore we propose that therapeutic targeting of autophagy pathways may reduce beta cell death in type 1 diabetes development.

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Section: Discussionmentioning

confidence: 50%

Pancreatic Beta Cell Autophagy is Impaired in Type 1 Diabetes

Muralidharan

Conteh

Marasco

et al. 2020

Preprint

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“…Deactivation mutations within PTEN lead to the sustained signaling of the PI3K/AKT/mTOR pathway (69, 72) via constitutive AKT activation. These mutations are less frequent in pHGG (5%-15% of cases) than in aHGG with loss of heterozygosity (LOH) observed in <30% of cases (19,73,74). However, PTEN promoter methylation, leading to decreased PTEN protein expression has been reported for pHGG (75).…”

Section: Regulation Of the Pi3k/akt/mtor Network By Ptenmentioning

confidence: 99%

Modulating autophagy as a therapeutic strategy for the treatment of paediatric high‐grade glioma

et al. 2019

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Paediatric high‐grade gliomas (pHGG) represent a therapeutically challenging group of tumors. Despite decades of research, there has been minimal improvement in treatment and the clinical prognosis remains poor. Autophagy, a highly conserved process for recycling metabolic substrates is upregulated in pHGG, promoting tumor progression and evading cell death. There is significant crosstalk between autophagy and a plethora of critical cellular pathways, many of which are dysregulated in pHGG. The following article will discuss our current understanding of autophagy signaling in pHGG and the potential modulation of this network as a therapeutic target.

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“…Numerous studies demonstrate that ER stress plays an important role in many diseases, including hemorrhage stroke, other inflammatory and metabolic diseases [21,22,23]. In addition, emerging evidence suggests that ER stress can trigger autophagy [24,25,26].…”

Section: Introductionmentioning

confidence: 99%

Heme induces autophagic cell death via ER stress in neuron

Yang

Huang

Tang

et al. 2019

Preprint

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Aims Intracerebral hemorrhage (ICH) is serious medical problem and the effective treatment is limited. Hemorrhaged blood is highly toxic to the brain, and heme mainly released from hemoglobin plays a vital role in neurotoxicity. However, the specific mechanism involved in heme mediated neurotoxicity has not been well studied.Methods In this study, we investigated the neurotoxicity of heme in neurons. Neurons were administrated with heme, and the cell death, autophagy and ER stress were analyzed. In addition, the relationship between autophagy and apoptosis in heme-induced cell death and the downstream effects were also detected.Results We showed that heme induced cell death and autophagy in neurons. The suppression of autophagy using either pharmacologic inhibitors (3-methyladenine) or RNA interference in essential autophagy genes (BECN1 and ATG5) decreased the cell death induced by heme in neurons. Moreover, ER stress activator thapsigargin increased the cell autophagy and cell death ratio following heme treatment. Autophagy promotes cell apoptosis and cell death induced by heme through BECN1/ ATG5 pathway.Conclusions Our findings suggest that heme potentiates neuron autophagy via ER stress, in turn inducing cell death via BECN1/ATG5 pathway. Targeting ER stress mediated autophagy might be a promising therapeutic strategy for ICH.

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Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis

Cited by 68 publications

References 54 publications

Pancreatic Beta Cell Autophagy is Impaired in Type 1 Diabetes

Pancreatic Beta Cell Autophagy is Impaired in Type 1 Diabetes

Modulating autophagy as a therapeutic strategy for the treatment of paediatric high‐grade glioma

Heme induces autophagic cell death via ER stress in neuron

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