Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation DOI Open Access
Gumpei Yoshimatsu, Faisal Kunnathodi, Prathab Balaji Saravanan

et al.

Diabetes, Journal Year: 2017, Volume and Issue: 66(11), P. 2857 - 2867

Published: Aug. 30, 2017

Pancreatic islets produce and secrete cytokines chemokines in response to inflammatory metabolic stress. The physiological role of these “isletokines” health disease is largely unknown. We observed that release multiple mediators patients undergoing islet transplants within hours infusion. proinflammatory cytokine interferon-γ–induced protein 10 (IP-10/CXCL10) was among the highest released, high levels correlated with poor transplant outcomes. Transgenic mouse studies confirmed donor islet–specific expression IP-10 contributed inflammation loss β-cell function grafts. effects islet-derived could be blocked by treatment recipient mice anti–IP-10 neutralizing monoclonal antibody. In vitro showed induction gene mediated calcineurin-dependent NFAT signaling pancreatic β-cells oxidative or Sustained association p300 histone acetyltransferase required p38 c-Jun N-terminal kinase mitogen-activated (MAPK) activity, which differentially regulated subsequent release. Overall, findings elucidate an NFAT-MAPK paradigm for isletokine reveal as a primary therapeutic target prevent β-cell–induced graft after cell transplantation.

Language: Английский

Inflammation in obesity, diabetes, and related disorders DOI Creative Commons
Theresa V. Rohm, Daniel T. Meier, Jerrold M. Olefsky

et al.

Immunity, Journal Year: 2022, Volume and Issue: 55(1), P. 31 - 55

Published: Jan. 1, 2022

Language: Английский

Citations

1181
Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation DOI
Erez Dror, Élise Dalmas, Daniel T. Meier

et al.

Nature Immunology, Journal Year: 2017, Volume and Issue: 18(3), P. 283 - 292

Published: Jan. 16, 2017

Language: Английский

Citations

339
Islet inflammation in type 2 diabetes and physiology DOI Open Access

Kosei Eguchi,

Ryozo Nagai

Journal of Clinical Investigation, Journal Year: 2017, Volume and Issue: 127(1), P. 14 - 23

Published: Jan. 2, 2017

The finding of islet inflammation in type 2 diabetes (T2D) and its involvement β cell dysfunction has further highlighted the significance metabolic diseases. number intra-islet macrophages is increased T2D, these cells are main source proinflammatory cytokines within islets. Multiple human studies T2D have shown that targeting potential to be an effective therapeutic strategy. In this Review we provide overview cellular molecular mechanisms by which develops causes dysfunction. We also emphasize regulation roles macrophage polarity shift islets context pathology health, may broad translational implications for therapeutics aimed at improving function.

Language: Английский

Citations

299
The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities DOI
Wei Ying, Wenxian Fu, Yun Sok Lee

et al.

Nature Reviews Endocrinology, Journal Year: 2019, Volume and Issue: 16(2), P. 81 - 90

Published: Dec. 13, 2019

Language: Английский

Citations

290
Islet inflammation in type 2 diabetes DOI Creative Commons
Marianne Böni‐Schnetzler, Daniel T. Meier

Seminars in Immunopathology, Journal Year: 2019, Volume and Issue: 41(4), P. 501 - 513

Published: April 15, 2019

Metabolic diseases including type 2 diabetes are associated with meta-inflammation. β-Cell failure is a major component of the pathogenesis diabetes. It now well established that increased numbers innate immune cells, cytokines, and chemokines have detrimental effects on islets in these chronic conditions. Recently, evidence emerged which points to initially adaptive restorative functions inflammatory factors cells metabolism. In following review, we provide an overview features islet inflammation models prediabetes. We separately emphasize what known humans focus vivo animal how they used elucidate mechanistic aspects inflammation. Further, discuss recently emerging physiologic signaling role cytokines during adaptation normal function cells.

Language: Английский

Citations

176
The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging DOI Creative Commons
Allison K. Meyers, Xuewei Zhu

Cells, Journal Year: 2020, Volume and Issue: 9(8), P. 1808 - 1808

Published: July 30, 2020

In response to inflammatory stimuli, immune cells reconfigure their metabolism and bioenergetics generate energy substrates for cell survival launch effector functions. As a critical component of the innate system, nucleotide-binding oligomerization domain, leucine-rich repeat, pyrin domain-containing 3 (NLRP3) inflammasome can be activated by various endogenous exogenous danger signals. Activation this cytosolic multiprotein complex triggers release pro-inflammatory cytokines interleukin (IL)-1β IL-18 initiates pyroptosis, an form programmed death. The NLRP3 fuels both chronic acute conditions is in emergence inflammaging. Recent advances have highlighted that metabolic pathways converge as potent regulators inflammasome. This review focuses on our current understanding regulation activation, contribution

Language: Английский

Citations

148
Repression of latent NF-κB enhancers by PDX1 regulates β cell functional heterogeneity DOI Creative Commons
Benjamin J. Weidemann, Biliana Marcheva, Mikoto Kobayashi

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(1), P. 90 - 102.e7

Published: Jan. 1, 2024

Interactions between lineage-determining and activity-dependent transcription factors determine single-cell identity function within multicellular tissues through incompletely known mechanisms. By assembling a atlas of chromatin state human islets, we identified β cell subtypes governed by either high or low activity the factor pancreatic duodenal homeobox-1 (PDX1). cells with reduced PDX1 displayed increased accessibility at latent nuclear κB (NF-κB) enhancers. Pdx1 hypomorphic mice exhibited de-repression NF-κB impaired glucose tolerance night. Three-dimensional analyses in tandem immunoprecipitation (ChIP) sequencing revealed that silences circadian inflammatory enhancers long-range contacts involving SIN3A. Conversely, Bmal1 ablation disrupted genome-wide DNA binding. Finally, antagonizing interleukin (IL)-1β receptor, an target, improved insulin secretion islets. Our studies reveal functional single defined gradient identify as target for insulinotropic therapy.

Language: Английский

Citations

19
Cystic fibrosis–related diabetes is caused by islet loss and inflammation DOI Open Access
Nathaniel Hart,

Radhika Aramandla,

Gregory Poffenberger

et al.

JCI Insight, Journal Year: 2018, Volume and Issue: 3(8)

Published: April 18, 2018

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

Language: Английский

Citations

154
Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity DOI Creative Commons
Lucie Orliaguet, Élise Dalmas,

Karima Drareni

et al.

Frontiers in Endocrinology, Journal Year: 2020, Volume and Issue: 11

Published: Feb. 19, 2020

Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section these etiologies lays phenomenon inflammation. Whilst inflammation characterized as systemic, common starting point tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines course severity. This review will highlight key mechanisms in macrophage polarization, inflammatory non-inflammatory signaling that dictates development progression insulin resistance T2D. We first describe known homeostatic functions tissue macrophages secreting major sensitive tissues. Importantly we activation tissues ways which this leads impairment sensitivity/secretion next cellular are dictate polarization. recent progress bio-energetics, an emerging field research places metabolism at center immune-effector function. Importantly, following advent metabolically-activated cover transcriptional epigenetic factors canonically non-canonically differentiation In closing perspectives, discuss themes novel non-immune roles have maintaining microenvironmental systemic homeostasis.

Language: Английский

Citations

108
Expression of miRNA-29 in Pancreatic β Cells Promotes Inflammation and Diabetes via TRAF3 DOI Creative Commons
Yi Sun,

Yuncai Zhou,

Ying Shi

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 34(1), P. 108576 - 108576

Published: Jan. 1, 2021

Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by insulin resistance and pancreatic β cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report key cell-macrophage crosstalk pathway mediated miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance when fed high-fat diet (HFD). The metabolic effect of miR-29 largely through macrophages because either depletion or reconstitution with miR-29-signaling defective bone marrow improves parameters in mice. Mechanistically, our data show that promotes recruitment activation circulating monocytes and, hence, inflammation, via exosomes TRAF3-dependent manner. Our results demonstrate ability cells modulate systemic tone homeostasis response nutrient overload.

Language: Английский

Citations

105