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Expansion of Islet-Resident Macrophages Leads to Inflammation Affecting Beta Cell Proliferation and Function in Obesity

ABSTRACT: Expansion of Islet-Resident Macrophages Leads to Inflammation Affecting Beta Cell Proliferation and Function in Obesity

PROVIDER: PRJNA438927 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6855580.fastq.gz	Fastqsanger.gz
	SRR6855581.fastq.gz	Fastqsanger.gz
	SRR6855582.fastq.gz	Fastqsanger.gz
	SRR6855583.fastq.gz	Fastqsanger.gz
	SRR6855584.fastq.gz	Fastqsanger.gz

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Expansion of Islet-Resident Macrophages Leads to Inflammation Affecting Beta Cell Proliferation and Function in Obesity

Project description:Inflammation is a key component of the pathogenesis of obesity-associated type 2 diabetes (T2D). However, the nature of T2D-associated islet inflammation and its impacts on T2D-associated beta cell abnormalities remain poorly defined. Using both diet-induced and genetically modified T2D animal models, we explore immune components of islet inflammation and define their roles in regulating beta cell function and proliferation. Our studies show that T2D-associated islet inflammation is uniquely dominated by macrophages, without the involvement of adaptive immune cells. We identify two islet macrophage populations, characterized by their distinct phenotypes, anatomical distributions and functional properties. Obesity induces a local expansion of intra-islet macrophages, independent of the replenishment from circulating monocytes. In contrast, the abundance of peri-islet macrophages is negligibly affected by obesity. Functionally, intra-islet macrophages impair beta cell function in a cell-cell contact dependent manner. In contrast, both intra- and peri-islet macrophage populations are able to promote beta cell proliferation. Together, these data provide a definitive view of the genesis of T2D-associated islet inflammation and define specific roles of islet macrophages in regulating beta cell function and proliferation.

2019-01-02 | GSE112002 | GEO

Expansion of Islet-Resident Macrophages Leads to Inflammation Affecting β Cell Proliferation and Function in Obesity.

Project description:The nature of obesity-associated islet inflammation and its impact on β cell abnormalities remains poorly defined. Here, we explore immune cell components of islet inflammation and define their roles in regulating β cell function and proliferation. Islet inflammation in obese mice is dominated by macrophages. We identify two islet-resident macrophage populations, characterized by their anatomical distributions, distinct phenotypes, and functional properties. Obesity induces the local expansion of resident intra-islet macrophages, independent of recruitment from circulating monocytes. Functionally, intra-islet macrophages impair β cell function in a cell-cell contact-dependent manner. Increased engulfment of β cell insulin secretory granules by intra-islet macrophages in obese mice may contribute to restricting insulin secretion. In contrast, both intra- and peri-islet macrophage populations from obese mice promote β cell proliferation in a PDGFR signaling-dependent manner. Together, these data define distinct roles and mechanisms for islet macrophages in the regulation of islet β cells.

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Hyperglycemia Alters the Fetal Islet Transcriptome and Leads to Progeny Islet Dysfunction

Project description:Hyperglycemia Alters the Fetal Islet Transcriptome and Leads to Progeny Islet Dysfunction

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Identification of cis-regulatory elements affecting pancreatic Islet maturation using chromatin accessibility variations

Project description:Identification of cis-regulatory elements affecting pancreatic Islet maturation using chromatin accessibility variations

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ARID1A loss in pancreas leads to islet developmental defect and metabolic disturbance ,Islet cell ChIP-Seq HDAC6 arid1a

Project description:ARID1A loss in pancreas leads to islet developmental defect and metabolic disturbance ,Islet cell ChIP-Seq HDAC6 arid1a

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The human and mouse islet peptidome: effects of obesity and type 2 diabetes

Project description:To characterise the impact of metabolic disease on the peptidome of human and mouse pancreatic islets and the contribution of intra-islet glucagon-like peptide 1 (GLP-1) receptor signalling.

2021-08-24 | PXD026095 | Pride

The role of CFTR in islet function

Project description:Cystic fibrosis (CF)-related diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting ~35% of adults with CF. However, the underlying causes of CFRD are unclear. Here, we examined cystic fibrosis transmembrane conductance regulator (CFTR) islet expression and whether the CFTR participates in islet endocrine cell function using murine models of b cell CFTR deletion, and normal and CF human pancreas and islets. Specific deletion of CFTR from murine b cells did not affect b cell function. In human islets, CFTR mRNA was minimally expressed, and CFTR protein/electrical activity was not detected. Isolated CF/CFRD islets demonstrated appropriate insulin and glucagon secretion with few changes in key islet-regulatory transcripts. Furthermore, ~65% of b cell area was lost in CF donors, compounded by pancreatic remodeling and immune infiltration of the islet. These results indicate that CFRD is not caused by intrinsic islet dysfunction from CFTR mutation, but rather, by b cell loss and intra-islet inflammation in the setting of a complex pleiotropic disease

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Project description:ARID1A is a tumor suppressor gene mutated in 7-10% of pancreatic cancer patients. However, its function in pancreas development and endocrine regulation is unclear. We generated mice that lack Arid1a expression in the pancreas. Our results showed that deletion of the Arid1a gene in mice caused a reduction in islet numbers and insulin production, both of which are associated with diabetes mellitus (DM) phenotype.we performed chromatin immunoprecipitation-sequencing analysis (ChIP-seq) to study genome-wide HDAC6 occupancy in the control and Arid1a-depleted islet cells.

2022-12-11 | GSE220638 | GEO

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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.

2021-02-11 | GSE166572 | GEO

Islet Sympathetic Innervation and Islet Neuropathology in Patients with Type 1 Diabetes

Project description:Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac b-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.

2021-08-09 | GSE181674 | GEO

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