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12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice

ABSTRACT: Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12gene. Our findings demonstrate that VLX-1005, a potent 12-LOX inhibitor, effectively delays the onset of autoimmune diabetes in human gene replacement non-obese diabetic (NOD) mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecules PD-L1 and PD-1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets from inhibitor-treated mice revealed significant alteration of cytokine-responsive pathways. RNA sequencing of polarized proinflammatory macrophages showed that VLX-1005 significantly reduced the interferon response. This study highlights a functional equivalence of human ALOX12 and mouse Alox15 in T1D pathogenesis. Our studies provide a platform for the preclinical evaluation of LOX inhibitors and supports the development of 12-LOX inhibitors as a therapeutic strategy for T1D and other inflammatory diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE272668 | GEO | 2024/08/23

REPOSITORIES: GEO

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12-Lipoxygenase Inhibition Suppresses Islet Immune and Inflammatory Responses and Delays Autoimmune Diabetes in Human Gene Replacement Mice.

Project description:Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12gene. Our findings demonstrate that VLX-1005, a potent 12-LOX inhibitor, effectively delays the onset of autoimmune diabetes in human gene replacement non-obese diabetic (NOD) mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecules PD-L1 and PD-1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets from inhibitor-treated mice revealed significant alteration of cytokine-responsive pathways. RNA sequencing of polarized proinflammatory macrophages showed that VLX-1005 significantly reduced the interferon response. This study highlights a functional equivalence of human ALOX12 and mouse Alox15 in T1D pathogenesis. Our studies provide a platform for the preclinical evaluation of LOX inhibitors and supports the development of 12-LOX inhibitors as a therapeutic strategy for T1D and other inflammatory diseases.

2024-08-23 | GSE272687 | GEO

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

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.

2021-02-11 | GSE166572 | GEO

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

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.

2017-10-29 | GSE101722 | GEO

Genome-Wide Gene Expression Profiles in the Pancreatic Lymph Nodes of non-obese diabetic (NOD) mice

Project description:Type 1 diabetes (T1D) is a polygenic autoimmune disorder caused by autoreactive T cells that recognize pancreatic islet antigens and subsequently destroy insulin-producing β-cells. Pancreatic lymph nodes (PLN) are an essential site for the development of T1D, where tolerance to pancreatic self-antigens is first broken and the autoimmune responses are amplified. The purpose of this study was to identify candidate genes and pathways in the PLN that may contribute to the pathogenesis of T1D using a mouse model of T1D. Genome-wide gene expression was measured in individual NOD PLN at 10 days (n=6), 4 weeks (n=6) or 12 weeks of age (n=5), against a pooled sample of age-matched NOD.B10 PLN as the control (n≥6), using Agilent Whole Mouse Genome Microarrays.

2015-03-09 | E-GEOD-66658 | biostudies-arrayexpress

RNA-Seq of wounds comparing gene expression in wild type and Alox15 deficient mice during day 0, day 4 and day 7 post-wounding.

Project description:Alox15 is a gene which encodes 12/15-LOX, an enzyme that generates bioactive lipid mediators. This experiment is designed to look at the impact of genetic deletion of Alox15 in punch wounds in skin, in order to determine how the protein may be involved in regulating wound healing. Punch wounds were generated on skin of wild type (C57BL/6) and Alox15 deficient mice, which were then allowed to heal for up to 7 days. Samples were obtained at varying time points for RNASeq analysis. Group sizes were 4 for each strain and at each time point. Following processing, one wild type (WT-d0-br3) sample failed a quality control check (Alox15 gene expression data indicated it was a knockout sample) and was removed from further analysis. Users may wish to remove this sample before re-using the dataset.

2023-06-21 | E-MTAB-12845 | biostudies-arrayexpress

10X single-cell RNA-seq profiling of T cells from the pancreas, pancreatic lymph nodes, and blood of NOD mice with spontaneous or anti-PD-1-induced Type 1 Diabetes

Project description:Immune-related adverse events (irAEs) are a notable complication of PD-1 cancer immunotherapy. A better understanding of how these iatrogenic diseases compare to naturally arising autoimmune diseases is needed for treatment and monitoring of irAEs. We identified differences in anti-PD-1-induced Type 1 Diabetes (T1D) and spontaneous T1D in non-obese diabetic (NOD) mice by performing single-cell RNA-seq and TCR-seq on T cells from the pancreas, pancreas-draining lymph node (pLN), and blood of mice with PD-1-induced T1D or spontaneous T1D. In the pancreas, anti-PD-1 resulted in expansion of terminally-exhausted/effector-like CD8+ T cells, an increase in T-bethi CD4+FoxP3- T cells, and a decrease in memory CD4+FoxP3- and CD8+ T cells in contrast to spontaneous T1D. Notably, anti-PD-1 caused increased TCR sharing between the pancreas and the periphery. Moreover, T cells in the blood of anti-PD-1-treated mice expressed markers that differed from spontaneous T1D, suggesting that the blood may provide a window to monitor irAEs rather than relying exclusively on the autoimmune target organ.

2023-07-05 | GSE228233 | GEO

Proteome and (ox)PTP profile analysis of diabetic NOD mouse under single (anti-CD3) or combined (anti-CD3 + IL1RA) treatment

Project description:Type 1 diabetes (T1D) results from autoimmune destruction of β cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell function. Here, we assessed the global protein and individual PTP profile in the pancreas of diabetic NOD mice treated with anti-CD3 mAb and IL-1RA combination therapy. The treatment reversed hyperglycemia compared to the anti-CD3 alone control group. We observed enhanced expression of PTPN2, a T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the islets from cured mice.

2022-11-10 | PXD025394 | Pride

Transcription profiling human whole blood from children with pre-type1diabetes

Project description:Type 1 diabetes (T1D) is an autoimmune disease caused by selective destruction of insulin producing pancreatic beta-cells in the islets of the Langerhans. The progression to clinical diabetes is characterized by the appearance of autoantibodies against islet cells (ICA) and beta-cell-specific antigens (IAA, IA-2 and GADA), which are considered the first markers signifying onset of autoimmunity. The mechanisms initiating or enhancing the autoimmune process remain poorly understood. Transcriptomic profiling on whole blood samples provides an approach for monitoring T1D disease process. In these investigations of pathways that are changed during the disease process, we have analyzed RNA from longitudinal peripheral blood samples of children who have developed T1D associated autoantibodies and eventually clinical type 1 diabetes . All study subjects were participants of the Type 1 Diabetes Prediction and Prevention (DIPP) study in Finland (38). Whole-blood RNA samples were collected during periodic clinic visits, typically at 3 to 12 month intervals. 2.5 ml venous blood was drawn into PAXgene Blood RNA tubes (Becton-Dickinson) and stored at -70°C. T1D-associated autoantibodies were measured from blood samples taken at each visit. Prospective samples from 3 children who developed T1D (subjects T1D_1 - T1D_3) and 2 children who developed ICA (subjects ICA_1 and ICA_2) during the DIPP follow-up were selected to the present study. Control children for the T1D cases (subjects T1D_C1 - T1D_C2) were matched for age, gender, birth place and HLA-genotype, from families who have no first-degree relatives with T1D. All samples (n=60) were processed and hybridized on Affymetrix Human Genome U133 Plus 2.0 arrays.

2010-03-31 | E-TABM-666 | biostudies-arrayexpress

Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Project description:Prevention or delay of autoimmune type 1 diabetes (T1D) onset is possible if molecular triggering events can be pharmacologically targeted. The integrated stress response (ISR) is activated during cellular stress to halt protein production and redirect energy towards cellular survival temporarily. We hypothesized that the activity of the ISR in the insulin-producing β cell during T1D becomes maladaptive and renders the cell prone to autoimmunity. We show that suppression of the ISR by using a novel inhibitor of the kinase PERK reverses the translation initiation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves β cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice shows reductions in the unfolded protein response and PERK signaling pathways and alterations in antigen processing and presentation pathways in β cells. Spatial proteomics analysis of islets from these mice shows a post-transcriptional increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following ISR inhibition in human islets and EndoC-βH1 human β cells, interacts with and post-transcriptionally stabilizes PD-L1. Collectively, our studies show that the ISR, mediated by PERK, enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.

2024-06-05 | GSE245004 | GEO

Genome-Wide Gene Expression Profiles in the Pancreatic Lymph Nodes of At-Risk Autoantibody Positive Individuals

Project description:Type 1 diabetes (T1D) is a polygenic autoimmune disorder caused by autoreactive T cells that recognize pancreatic islet antigens and subsequently destroy insulin-producing β-cells. Pancreatic lymph nodes (PLN) are an essential site for the development of T1D, where tolerance to pancreatic self-antigens is first broken and the autoimmune responses are amplified. The purpose of this study was to identify candidate genes and pathways in the PLN that may contribute to the pathogenesis of T1D. Microarray analysis was performed on the PLN of human non-diabetic healthy controls (n=7) and at-risk autoantibody-positive subjects (n=13).

2015-03-03 | E-GEOD-66413 | biostudies-arrayexpress

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