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

ABSTRACT: Type 1 diabetes (T1D) results from ?-cell destruction due to concerted action of both innate and adaptive immune responses. Pro-inflammatory cytokines, such as interleukin-1? and interferon-?, secreted by the immune cells invading islets of Langerhans, contribute to pancreatic ?-cell death in T1D. Cytokine-induced endoplasmic reticulum (ER) stress plays a central role in ?-cell demise. ER stress can modulate autophagic response; however, no study addressed the regulation of autophagy during the pathophysiology of T1D. In this study, we document that cytokines activate the AMPK-ULK-1 pathway while inhibiting mTORC1, which stimulates autophagy activity in an ER stress-dependent manner. On the other hand, time-course analysis of LC3-II accumulation in autophagosomes revealed that cytokines block the autophagy flux in an ER stress independent manner, leading to the formation of large dysfunctional autophagosomes and worsening of ER stress. Cytokines rapidly impair lysosome function, leading to lysosome membrane permeabilization, Cathepsin B leakage and lysosomal cell death. Blocking cathepsin activity partially protects against cytokine-induced or torin1-induced apoptosis, whereas blocking autophagy aggravates cytokine-induced CHOP overexpression and ?-cell apoptosis. In conclusion, cytokines stimulate the early steps of autophagy while blocking the autophagic flux, which aggravate ER stress and trigger lysosomal cell death. Restoration of autophagy/lysosomal function may represent a novel strategy to improve ?-cell resistance in the context of T1D.

SUBMITTER: Lambelet M

PROVIDER: S-EPMC5833699 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Lambelet Martine M Terra Leticia F LF Fukaya Makiko M Meyerovich Kira K Labriola Leticia L Cardozo Alessandra K AK Allagnat Florent F

Cell death & disease 20180124 2

Type 1 diabetes (T1D) results from β-cell destruction due to concerted action of both innate and adaptive immune responses. Pro-inflammatory cytokines, such as interleukin-1β and interferon-γ, secreted by the immune cells invading islets of Langerhans, contribute to pancreatic β-cell death in T1D. Cytokine-induced endoplasmic reticulum (ER) stress plays a central role in β-cell demise. ER stress can modulate autophagic response; however, no study addressed the regulation of autophagy during the ...[more]

PMID: 29367588

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Project description:Repetitive or overuse disorders of the lumbar spine affect the lives of workers and athletes. We hypothesize that repetitive anterior lumbar flexion-extension under low or high load will result in significantly elevated pro-inflammatory cytokines expression several hours post-activity. High loads will exhibit significantly higher expression than low loads. Lumbar spine of in vivo feline was subjected to cyclic loading at 0.25 Hz for six 10-min periods with 10 min of rest in between. One group was subjected to a low peak load of 20 N, whereas the second group to a high peak load of 60 N. Following a 7-h post-loading rest, the supraspinous ligaments of L-3/4, L-4/5 and L-5/6 and the unstimulated T-10/11 were excised for mRNA analysis and IL-1beta, IL-6, IL-8, TNFalpha and TGFbeta1 pro-inflammatory cytokines expression. Creep (laxity) developed in the lumbar spine during the loading and the subsequent 7 h of rest was calculated. A two-way mixed model ANOVA was used to assess difference in each cytokines expression between the two groups and control. Tukey HSD post hoc analysis delineated specific significant effects. Significance was set at 0.05. Low and high-load groups exhibited development of creep throughout the cyclic loading period and gradual recovery throughout the 7-h rest period. Residual creep of 24.8 and 30.2% were present in the low and high-load groups, respectively, 7-h post-loading. Significant increases in expression of all cytokines measured relative to control were obtained for supraspinous ligaments from both low and high-load magnitudes. IL-6, IL-8 and TGFbeta1 expression in the high-load group were significantly higher relative to the low-load group. Significant increases in cytokines expression indicating tissue inflammation are observed several hours post-repetitive lumbar flexion-extension regardless of the load magnitude applied. Repetitive occupational and athletic activity, regardless of the load applied, may be associated with the potential of developing acute inflammatory conditions that may convert to chronic inflammation if the viscoelastic tissues are further exposed to repetitive activity over long periods. Appropriate rest periods are a relevant preventive measure.

Dataset Information

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

Publications

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

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