An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis.
An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis.
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DOI：
10.1016/j.molmet.2021.101365
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发表时间：
2021-12
影响因子：
8.1
通讯作者：
Engin F
中科院分区：
文献类型：
--
作者：
Sahin GS;Lee H;Engin F
胰腺β细胞是生物体的胰岛素工厂，其使命是调节体内葡萄糖稳态。由于它们的高分泌活性，β细胞依赖于功能性和完整的内质网（ER）。ER稳态的扰动和未减轻的应激导致β细胞功能障碍和死亡。1型糖尿病（T1D）是一种由自身免疫介导的β细胞破坏引起的慢性炎症性疾病。尽管自身免疫是T1D发病机制的重要组成部分，但越来越多的证据表明β细胞ER应激和异常未折叠蛋白反应（UPR）在疾病的发生和进展中起重要作用。本文介绍了ER应激和UPR，综述了各种小鼠模型中的β细胞ER应激，评价了其在炎症中的作用，并讨论了ER应激对T1D中β细胞可塑性和死亡以及胰岛自身免疫的影响。我们还强调了ER应激与其他应激反应途径的关系，并为正在进行的针对ER应激和UPR预防或治疗T1D的临床研究提供了见解。来自离体研究、体内小鼠模型和患者组织样本的证据表明，β细胞ER应激和缺陷性UPR有助于T1D发病机制。因此，在疾病的各个阶段恢复β细胞ER稳态为T1D提供了一种合理的治疗策略。确定β细胞中每个UPR传感器的特定功能和调节，并揭示T1D进展期间应激β细胞和免疫细胞之间的串扰，将提供对疾病过程的分子机制的更好理解，并可能揭示开发T1D有效疗法的新靶点。
Pancreatic β-cells are the insulin factory of an organism with a mission to regulate glucose homeostasis in the body. Due to their high secretory activity, β-cells rely on a functional and intact endoplasmic reticulum (ER). Perturbations to ER homeostasis and unmitigated stress lead to β-cell dysfunction and death. Type 1 diabetes (T1D) is a chronic inflammatory disease caused by the autoimmune-mediated destruction of β-cells. Although autoimmunity is an essential component of T1D pathogenesis, accumulating evidence suggests an important role of β-cell ER stress and aberrant unfolded protein response (UPR) in disease initiation and progression. In this article, we introduce ER stress and the UPR, review β-cell ER stress in various mouse models, evaluate its involvement in inflammation, and discuss the effects of ER stress on β-cell plasticity and demise, and islet autoimmunity in T1D. We also highlight the relationship of ER stress with other stress response pathways and provide insight into ongoing clinical studies targeting ER stress and the UPR for the prevention or treatment of T1D. Evidence from ex vivo studies, in vivo mouse models, and tissue samples from patients suggest that β-cell ER stress and a defective UPR contribute to T1D pathogenesis. Thus, restoration of β-cell ER homeostasis at various stages of disease presents a plausible therapeutic strategy for T1D. Identifying the specific functions and regulation of each UPR sensor in β-cells and uncovering the crosstalk between stressed β-cells and immune cells during T1D progression would provide a better understanding of the molecular mechanisms of disease process, and may reveal novel targets for development of effective therapies for T1D.