Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis.
Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis.
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暴露于促炎细胞因子后的功能障碍性自噬有助于胰腺β细胞凋亡。
DOI：
10.1038/s41419-017-0121-5
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发表时间：
2018-01-24
影响因子：
9
通讯作者：
Allagnat F
中科院分区：
文献类型：
--
作者：
Lambelet M;Terra LF;Fukaya M;Meyerovich K;Labriola L;Cardozo AK;Allagnat F
1型糖尿病（T1 D）是由于先天性和适应性免疫反应的协同作用而导致的β细胞破坏。由侵入胰岛的免疫细胞分泌的促炎细胞因子，如白细胞介素-1 β和干扰素-γ，导致T1 D中的胰腺β细胞死亡。细胞因子诱导的内质网（ER）应激在β细胞死亡中起着重要作用。ER应激可以调节自噬反应，然而，没有研究解决T1 D的病理生理过程中的自噬调节。在这项研究中，我们记录了细胞因子激活AMPK-ULK-1通路，同时抑制mTORC 1，从而以ER应激依赖性方式刺激自噬活性。另一方面，LC 3-II在自噬体中积累的时程分析显示，细胞因子以不依赖于ER应激的方式阻断自噬通量，导致大的功能失调的自噬体的形成和ER应激的恶化。细胞因子迅速损害溶酶体功能，导致溶酶体膜透化、组织蛋白酶B渗漏和溶酶体细胞死亡。阻断组织蛋白酶活性可部分保护细胞免受苦参碱诱导或torin 1诱导的凋亡，而阻断自噬可抑制苦参碱诱导的CHOP过表达和β细胞凋亡。总之，细胞因子刺激自噬的早期步骤，同时阻断自噬通量，这加剧了ER应激并触发溶酶体细胞死亡。自噬/溶酶体功能的恢复可能代表在TlD背景下改善β细胞抗性的新策略。
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 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 β-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 β-cell resistance in the context of T1D.
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