Immune Context Governs Stage-Specific Responses to Depleting Anti-PD-1 Antibody in Type 1 Diabetes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE328069 | GEO | 2026/09/23
REPOSITORIES: GEO
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Project description:Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-lipoxygenase (12/15-LOX) is induced in β cells and macrophages during T1D and produces pro-inflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling suggested reduced promiscuity of ML351 compared to ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of pro-inflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the non-obese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in the insulitis. Our data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.
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Project description: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.
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Project description:The complex milieu of inflammatory mediators associated with many diseases is often too dilute to directly measure in the periphery, necessitating development of more sensitive measurements suitable for mechanistic studies, earlier diagnosis, guiding selection of therapy, and monitoring interventions. Previously, we determined that plasma of recent-onset (RO) Type 1 diabetes (T1D) patients induce a proinflammatory transcriptional signature in fresh peripheral blood mononuclear cells (PBMC) relative to that of unrelated healthy controls (HC). Here, using an optimized cryopreserved PBMC-based protocol, we analyzed larger RO T1D, HC, and healthy T1D sibling cohorts. In addition, we examined T1D progression by looking at longitudinal samples. UPN727 cells were stimulated with Auto-antibody-negative (AA-) High HLA Risk Siblings plasma (n=30), Auto-antibody-negative (AA-) Low HLA Risk Siblings plasma (n=42), Recent onset T1DM plasma cultured with IL1RA (n=42), or longitudinal series plasma on T1DM progressor (n=27 chips, 5 series), on auto-antibody-positive (AA+) High HLA Risk Siblings (n=54 chips, 9 series), on auto-antibody-negative (AA-) High HLA Risk Siblings (n=60 chips, 12 series), on auto-antibody-negative (AA-) Low HLA Risk Siblings (n=31 chips, 6 series). Gene expression analysis was perfromed in order to evaluate the transcriptional signature associated with T1D.
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2025-01-06 | GSE285039 | GEO
Project description:In type 1 diabetes (T1D), the innate and adaptive immune systems attack and eventually destroy the insulin-secreting islet β cells. During this process, β cells activate inflammatory signaling pathways that augment the dysfunction and destruction imposed by cellular autoimmunity. The 12-lipoxygenase (12-LOX) pathway produces the pro-inflammatory eicosanoid 12-HETE, which induces oxidative and endoplasmic reticulum stress and results in diminished insulin secretion and apoptosis. The G protein-coupled receptor 31 (GPR31) has been identified as a putative receptor for 12-HETE. In this study, we generated conventional GPR31 knockout mice. To interrogate the role of GPR31 in β cells, we treated islets from wildtype and Gpr31b-/- mice with proinflammatory cytokines and subjected the islets to RNA sequencing. Differentially expressed genes in Gpr31b-/- islets included those pertaining to receptor signaling, inflammation, oxidative stress, and macrophage migration — effects that are reminiscent of 12-LOX inhibition. Bone-marrow derived macrophages from Gpr31b-/- mice had reduced macrophage migration compared to wildtype macrophages. To mimic islet and macrophage inflammation as seen in T1D, wildtype and Gpr31b-/- mice were treated with the pro-diabetic toxin streptozotocin. Compared to wildtype, Gpr31b-/- mice had improved glucose tolerance and preserved β-cell mass. These results are consistent with previously published data using 12-LOX knockout mice and suggests that GPR31 mediates the proinflammatory responses of 12-HETE in the β cell.
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Project description:Type 1 diabetes (T1D) is an immune-mediated disease that leads to β cell dysfunction and death. However, the contribution of β cells in this process remains unclear. To understand how islet-derived pro-inflammatory signaling pathways contribute to diabetes pathogenesis, we generated inducible islet-specific Alox15 knockout mice on the NOD background. We report that islet-specific deletion of Alox15 induced a substantial increase of β-cell mass and decreased islet insulitis, and ultimately lead to a protection against spontaneous autoimmune diabetes in NOD mice. Single cell RNA-sequencing and mass spectrometry analysis revealed that islet-specific knockout of Alox15 leads to an increase of β cells expressing Pd-l1 and promotes an anti-inflammatory phenotype in myeloid cells and T cells inside the islets. Furthermore, islet- specific Alox15 deletion enhances the expansion of M2-like macrophages and regulatory T cells in the pancreatic islets and pancreatic lymph nodes. Together, these results lead to the conclusion that proinflammatory signals produced by β cells allows these cells to express immunoregulators that protects these cells of immune cell attack and promote β cell survival.
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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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Project description:This a model from the article:
Modelling the onset of Type 1 diabetes: can impaired macrophage phagocytosis make the difference between health and disease?
Maree AF, Kublik R, Finegood DT, Edelstein-Keshet L.Philos Transact A Math Phys Eng Sci.2006 May 15;364(1842):1267-82.
16608707,
Abstract:
A wave of apoptosis (programmed cell death) occurs normally in pancreatic beta-cells of newborn mice. We previously showed that macrophages from non-obese diabetic (NOD) mice become activated more slowly and engulf apoptotic cells at a lower rate than macrophages from control (Balb/c) mice. It has been hypothesized that this low clearance could result in secondary necrosis, escalating inflammation and self-antigen presentation that later triggers autoimmune, Type 1 diabetes (T1D). We here investigate whether this hypothesis could offer a reasonable and parsimonious explanation for onset of T1D in NOD mice. We quantify variants of the Copenhagen model (Freiesleben De Blasio et al. 1999 Diabetes 48, 1677), based on parameters from NOD and Balb/c experimental data. We show that the original Copenhagen model fails to explain observed phenomena within a reasonable range of parameter values, predicting an unrealistic all-or-none disease occurrence for both strains. However, if we take into account that, in general, activated macrophages produce harmful cytokines only when engulfing necrotic (but not apoptotic) cells, then the revised model becomes qualitatively and quantitatively reasonable. Further, we show that known differences between NOD and Balb/c mouse macrophage kinetics are large enough to account for the fact that an apoptotic wave can trigger escalating inflammatory response in NOD, but not Balb/c mice. In Balb/c mice, macrophages clear the apoptotic wave so efficiently, that chronic inflammation is prevented.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
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