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Early senescence-induced immunosuppressive β-cell secretome prevents type 1 diabetes

ABSTRACT: During the progression of type 1 diabetes (T1D), β-cells are exposed to significant stress and therefore require adaptive responses to survive. The adaptive mechanisms that can preserve β-cell function and survival in the face of autoimmunity remain unclear. Here we show that deletion of the unfolded protein response genes, Atf6α or Ire1α, in β-cells of NOD mice prior to insulitis generates a p21-driven early senescence phenotype and altered β-cell secretome that significantly enhances leukemia inhibitory factor-mediated recruitment of M2 macrophages to the islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause resolution of islet inflammation, removal of terminally senesced β-cells, reduction of β-cell apoptosis, and prevention of T1D. We further demonstrate that p21-mediated early senescence signature is conserved in residual β-cells of T1D patients. Our findings reveal a previously unrecognized link between β-cell UPR and senescence that, if leveraged, may represent a novel therapeutic strategy for T1D.

ORGANISM(S): Mus musculus

PROVIDER: GSE239947 | GEO | 2023/11/20

REPOSITORIES: GEO

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Stress-induced beta cell dedifferentiation prior to immune cell infiltration prevents type 1 diabetes [Single]

Project description:Immune-mediated destruction of insulin-producing β-cells causes type 1 diabetes (T1D). However, how β-cells themselves participate in the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in β-cells of non-obese diabetic (NOD) mice in early stages of disease results in preserved β-cell function, substantially reduced islet immune cell infiltration, and β-cell apoptosis leading to protection from T1D. NOD mice that lack the UPR sensor IRE1α in β-cells show greatly reduced expression of β-cell identity markers, islet autoantigens, and genes involved in antigen presentation. These mice exhibit upregulation of immune inhibitory markers in β-cells and significantly less cytotoxic CD8+ T cells in the pancreas. Our results indicate that triggering transient β-cell dedifferentiation via targeting a specific branch of the UPR in β-cells, prior to insulitis, allow β-cells to escape from immune destruction and may be used as a novel preventive strategy for high-risk individuals.

2020-01-30 | GSE144471 | GEO

Stress-induced beta cell dedifferentiation prior to immune cell infiltration prevents type 1 diabetes [Bulk]

2020-01-30 | GSE144461 | GEO

Islet-Autonomous Inflammatory Signaling Propagates Autoimmunity and Promotes Diabetes in Nonobese Diabetic Mice

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Inhibition of 12/15-Lipoxygenase Protects Against β Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

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2017-10-29 | GSE101722 | GEO

Wnt5A promotes an adaptive, senescent-like stress response, while continuing to drive invasion in melanoma cells.

Project description:We have previously shown that Wnt5A drives invasion in melanoma. We have also shown that Wnt5A promotes resistance to therapy designed to target the BRAF(V600E) mutation in melanoma. Here, we show that melanomas characterized by high levels of Wnt5A respond to therapeutic stress by increasing p21 and expressing classical markers of senescence, including positivity for senescence-associated β-galactosidase (SA-β-gal), senescence-associated heterochromatic foci (SAHF), H3K9Me chromatin marks, and PML bodies. We find that despite this, these cells retain their ability to migrate and invade. Further, despite the expression of classic markers of senescence such as SA-β-gal and SAHF, these Wnt5A-high cells are able to colonize the lungs in in vivo tail vein colony-forming assays. This clearly underscores the fact that these markers do not indicate true senescence in these cells, but instead an adaptive stress response that allows the cells to evade therapy and invade. Notably, silencing Wnt5A reduces expression of these markers and decreases invasiveness. The combined data point to Wnt5A as a master regulator of an adaptive stress response in melanoma, which may contribute to therapy resistance.

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Human Pancreatic Islets Expressing HNF1A Variant Have Defective β cell Transcriptional Regulatory Networks

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2018-09-22 | GSE120299 | GEO

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Project description:Type 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting β cells. In β cells, polyamines have been implicated in causing cellular stress and dysfunction. An inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), has been shown to delay T1D in mouse models and preserve β cell function in humans with recent-onset T1D. Another small molecule, N1,N11-diethylnorspermine (DENSpm), both inhibits polyamine biosynthesis and accelerates polyamine metabolism and is currently being tested for efficacy in cancer clinical trials. In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse β cells. RNA sequencing analysis, however, suggests that the cellular reponses to DENSpm and DFMO differ, with the two sharing similar effects on cellular proliferation, but the latter showing greater effects on mRNA translation and protein folding pathways. In the low-dose streptozotocin-induced mouse model of T1D, DENSpm administration did not prevent or delay diabetes outcome, but did result in improvements in glucose tolerance and reductions in islet oxidative stress. In non-obese diabetic (NOD) mice, short-term DENSpm administration resulted in slight reduction in insulitis and proinflammatory Th1 cells in the pancreatic lymph nodes. Longer term treatment resulted in a dose-dependent increase in mortality. Notwithstanding the efficacy of both DFMO and DENSpm in reducing potentially toxic polyamine levels in β cells, our results highlight the discordant T1D outcomes that result from differing mechanisms of polyamine depletion and, more importantly, that toxic effects of DENSpm may limit its utility in T1D treatment.

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