Pancreatic islet inflammation: an emerging role for chemokines

Collier, J. Jason; Sparer, Tim E.; Karlstad, Michael D.; Burke, Susan J.

doi:10.1530/jme-17-0042

Cited by 49 publications

(30 citation statements)

References 150 publications

(183 reference statements)

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“…In particular, the proinflammatory chemokine CXCL10 seems to be directly induced by acquisition of a senescent phenotype and is involved in the recruitment of autoreactive T‐lymphocytes in pancreatic islets, thus contributing to insulitis and β‐cell destruction. In accordance to these results, previous studies showed that CXCL10 is expressed in islet endocrine cells of T1D donors and plays a critical role in disease pathophysiology . Roep et al observed that the elevated levels of this chemokine in islets of recent‐onset T1D donors corresponded with the juxtaposed infiltration of lymphocytes bearing its cognate receptor CXCR3; of note, both CXCL10 + endocrine cells and CXCR3 + lymphocytes were undetectable in pancreas of non‐diabetic control donors .…”

Section: β‐Cell and α‐Cell Responses To Islet Inflammation In T1dsupporting

confidence: 77%

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

Nigi

Maccora

Dotta

et al. 2019

Diabetes Metabolism Res

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The histological analysis of human pancreatic samples in type 1 diabetes (T1D) has been proven essential to move forward in the evaluation of in situ events characterizing T1D. Increasing availability of pancreatic tissues collected from diabetic multiorgan donors by centralized biorepositories, which have shared tissues among researchers in the field, has allowed a deeper understanding of T1D pathophysiology, using novel immunohistological and high-throughput methods. In this review, we provide a comprehensive update of the main recent advancements in the characterization of cellular and molecular events involving endocrine and exocrine pancreas as well as the immune system in the onset and progression of T1D. Additionally, we underline novel elements, which provide evidence that T1D pathological changes affect not only islet β-cells but also the entire pancreas.

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Section: β‐Cell and α‐Cell Responses To Islet Inflammation In T1dsupporting

confidence: 77%

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

Nigi

Maccora

Dotta

et al. 2019

Diabetes Metabolism Res

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“…If true, this would explain why therapies targeting the IL-1 signaling pathway have shown either mixed results or limited efficacy during clinical trials. Indeed, macrophages and β-cells clearly have a symbiotic relationship, with macrophages responding to ATP release from β-cells and β-cells responding to cytokines produced and secreted by macrophages [54] , [55] .…”

Section: Discussionmentioning

confidence: 99%

Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet β-cell de-differentiation

Burke

Batdorf

Burk

et al. 2018

Molecular Metabolism

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ObjectivePancreatic tissue, and islets in particular, are enriched in expression of the interleukin-1 receptor type I (IL-1R). Because of this enrichment, islet β-cells are exquisitely sensitive to the IL-1R ligands IL-1α and IL-1β, suggesting that signaling through this pathway regulates health and function of islet β-cells.MethodsHerein, we report a targeted deletion of IL-1R in pancreatic tissue (IL-1RPdx1−/−) in C57BL/6J mice and in db/db mice on the C57 genetic background. Islet morphology, β-cell transcription factor abundance, and expression of the de-differentiation marker Aldh1a3 were analyzed by immunofluorescent staining. Glucose and insulin tolerance tests were used to examine metabolic status of these genetic manipulations. Glucose-stimulated insulin secretion was evaluated in vivo and in isolated islets ex vivo by perifusion.ResultsPancreatic deletion of IL-1R leads to impaired glucose tolerance, a phenotype that is exacerbated by age. Crossing the IL-1RPdx1−/− with db/db mice worsened glucose tolerance without altering body weight. There were no detectable alterations in insulin tolerance between IL-1RPdx1−/− mice and littermate controls. However, glucose-stimulated insulin secretion was reduced in islets isolated from IL-1RPdx1−/− relative to control islets. Insulin output in vivo after a glucose challenge was also markedly reduced in IL-1RPdx1−/− mice when compared with littermate controls. Pancreatic islets from IL-1RPdx1−/− mice displayed elevations in Aldh1a3, a marker of de-differentiation, and reduction in nuclear abundance of the β-cell transcription factor MafA. Nkx6.1 abundance was unaltered.ConclusionsThere is an important physiological role for pancreatic IL-1R to promote glucose homeostasis by suppressing expression of Aldh1a3, sustaining MafA abundance, and supporting glucose-stimulated insulin secretion in vivo.

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“…However, such inflammatory response is unlikely in our system with isolated islets. Instead, chemokines may interact with numerous chemokine receptors expressed on human islets and, in such way, trigger pathway signalling [ 36 , 37 ]. The mechanism of chemokine-induced signalling and its effect on insulin secretion is poorly investigated [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of early biological changes in palmitate-treated isolated human islets

Sargsyan¹,

Cen²,

Roomp³

et al. 2018

BMC Genomics

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BackgroundLong-term exposure to elevated levels of free fatty acids (FFAs) is deleterious for beta-cell function and may contribute to development of type 2 diabetes mellitus (T2DM). Whereas mechanisms of impaired glucose-stimulated insulin secretion (GSIS) in FFA-treated beta-cells have been intensively studied, biological events preceding the secretory failure, when GSIS is accentuated, are poorly investigated. To identify these early events, we performed genome-wide analysis of gene expression in isolated human islets exposed to fatty acid palmitate for different time periods.ResultsPalmitate-treated human islets showed decline in beta-cell function starting from day two. Affymetrix Human Transcriptome Array 2.0 identified 903 differentially expressed genes (DEGs). Mapping of the genes onto pathways using KEGG pathway enrichment analysis predicted four islet biology-related pathways enriched prior but not after the decline of islet function and three pathways enriched both prior and after the decline of islet function. DEGs from these pathways were analyzed at the transcript level. The results propose that in palmitate-treated human islets, at early time points, protective events, including up-regulation of metallothioneins, tRNA synthetases and fatty acid-metabolising proteins, dominate over deleterious events, including inhibition of fatty acid detoxification enzymes, which contributes to the enhanced GSIS. After prolonged exposure of islets to palmitate, the protective events are outweighed by the deleterious events, which leads to impaired GSIS.ConclusionsThe study identifies temporal order between different cellular events, which either promote or protect from beta-cell failure. The sequence of these events should be considered when developing strategies for prevention and treatment of the disease.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5008-z) contains supplementary material, which is available to authorized users.

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Pancreatic islet inflammation: an emerging role for chemokines

Cited by 49 publications

References 150 publications

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

From immunohistological to anatomical alterations of human pancreas in type 1 diabetes: New concepts on the stage

Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet β-cell de-differentiation

Identification of early biological changes in palmitate-treated isolated human islets

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