The maintenance of homeostasis by cells and organisms under stressful conditions is achieved through the activation of a highly conserved cellular stress response. Adaptive stress responses respond to stimuli and restore cellular homeostasis through a network of signaling mechanisms, but sustained and/or excessive stress responses can be harmful and even lead to apoptosis. Cellular stress usually affects multiple organelles simultaneously, triggering multiple stress responses. It's likely that the interactions, co-regulation, and non-cell-autonomous effects of these stress responses are very important in determining whether a response is adaptive or non-adaptive, but we still don't fully understand how these interactions work.
Endoplasmic reticulum (ER) stress is a type of cellular stress caused by the accumulation of unfolded proteins in the ER, viral infections, toxins, and chronic inflammation. ER stress triggers an unfolded protein response (UPR) to relieve stress and restore intracellular homeostasis. The The classical UPR is mediated by the activation of IRE1 (inositol-requiring protein-1), which is localized in the endoplasmic reticulum membrane, protein kinase RNA-like ER kinase (PERK), and activator of transcription-6 (ATF6), among others. PERK reduces most of the mRNA translation but can be specifically activated by PERK. PERK reduces the translation of most mRNAs but specifically induces the translation of the transcription factor Atf4, which regulates amino acid metabolism and the expression of genes related to oxidative stress reduction. Activation of IRE1a induces highly specific splicing of XBP1 mRNA, resulting in the production of spliced XBP1, a transcription factor regulating UPR target genes, which then regulates the expression of endoplasmic reticulum (ER)-associated protein degradation (ERAD) components and lipid biosynthesis enzyme transcription. ATF6 undergoes proteolytic cleavage in the Golgi and acts as an active transcription factor to up-regulate target genes encoding the ER molecule-associated degradation component, the ERAD component, and XBP1. Although the UPR initially attempts to promote cellular adaptation to ER stress, under sustained or severe stress, it induces a pro-apoptotic response that removes cells from the terminally stressed state.
Type 1 diabetes (T1D) pathogenesis is triggered by the initiation of an autoimmune process that results in almost complete death of pancreatic β-cells, leading to insulin deficiency. The important function of pancreatic β-cells in the initiation of their autoimmunity and the impact of aberrant stress responses on the disease progression of T1D have attracted considerable academic attention over the past decade. Early studies have shown that ER stress and UPR levels of β-cells are significantly elevated after exposure to inflammatory cytokines. Preclinical and clinical studies further confirmed that ER stress and UPR dysregulation in β-cells occurred before the onset of T1D. In preclinical models, T1D was effectively prevented by pharmacologically reducing ER stress and inhibiting IRE1a activity; however, the specific functions of other UPR sensors (ATF6 and PERK) in β-cells, the interactions between β-cells and immune cells, and their intricate relationship between ER stress and other cellular stress responses during the pathogenesis of autoimmune diseases are still poorly understood. poorly understood.
Senescence can be defined as a stress program initiated by the arrest of stably growing cells, mediated by cell cycle-dependent kinase inhibitory proteins (e.g., p21Cip1 and p16Ink4a), and involving a wide range of cellular changes, including anti-survival phenotypes and senescence-associated secretory phenotypes such as complex and dynamic secretions of growth factors, cytokines, chemokines, and other factors (senescence-associated secretory phenotype (SASP). SASP can initiate immune surveillance functions that can remove senescent cells from tissues and restore homeostasis; however, when the organism ages and the immune system is compromised, senescent cells accumulate, leading to tissue dysfunction. Notably, during natural aging in non-obese diabetic mice and human T1D, senescent β-cells accumulate and contribute to disease progression, and small molecule drugs targeting senescence can prevent T1D in NOD mice. In T1D, the accumulation of senescent β-cells with SASPs suggests dysfunctional immune surveillance. However, it remains unknown whether senescent β-cells can initiate immune surveillance functions. In addition, the correlation between senescence and other stress responses in β-cells is also unknown.
Recently, Feyza Engin's research group from the University of Wisconsin-Madison published an article in Cell Metabolism entitled Stress-induced b-cell early senescence confers protection against type 1 diabetes, which provides insights into the above question.
The authors first determined that in β-cells, knockdown of the key UPR molecules Atf6a or Ire1a leads to an early senescence program driven by p21, which generates a unique secretion that induces M2 macrophages to migrate into pancreatic islets. The end result is that M2 macrophages initiate anti-inflammatory effects, immunosuppressive responses, and immunosurveillance functions, with a marked reduction in terminally senescent β-cells, alleviation of pancreatic islet inflammation, reduction in β-cell apoptosis, and an increase in β-cell survival, which slows down the pathologic progression of T1D in the NOD mice.Analysis of single-cell transcriptome data from pancreatic islets of patients with T1D as well as the inhibition of human EndoC-βH1 cells and donor islets in the presence of ATF6 showed that p21-mediated early senescence was also characterized in residual β-cells from T1D patients.
This work reveals a novel link between β-cell UPR and senescence, which is likely to serve as a new strategy for restoring islet homeostasis and alleviating T1D.