Peripheral and Islet Interleukin-17 Pathway Activation Characterizes Human Autoimmune Diabetes and Promotes Cytokine-Mediated β-Cell Death

Arif, Sefina; Moore, Fabrice; Marks, Katherine; Bouckenooghe, Thomas; Dayan, Colin; Planas, Raquel; Vives-Pi, Marta; Powrie, Jake; Tree, Timothy; Marchetti, Piero; Huang, Guo Cai; Gurzov, Esteban Nicolas; Pujol-Borrell, Ricardo; Eizirik, Décio L.; Peakman, Mark

doi:10.2337/db10-1643

Cited by 189 publications

(188 citation statements)

References 37 publications

(53 reference statements)

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“…We have previously shown that IL-17A augments apoptosis in human islet cells or rat beta cells exposed to IL-1β+IFN-γ or TNF-α+INF-γ [17]. Here, these findings were expanded by the observations that IL-17A increased apoptosis induced by IL-1β+IFN-γ in rat INS-1E cells, as judged by nuclear dyes and caspase 3 cleavage (Fig.…”

Section: Il-17a Exacerbates Cytokine-induced Apoptosis In Rat Ins-1e supporting

confidence: 58%

“…Recent studies indicate an increased presence of Th17 cells among circulating T cells and in the pancreatic islets of type 1 diabetes patients [16][17][18][19]. Th17 cells secrete the cytokine IL-17A, which we and others have shown to exacerbate IL-1β+IFN-γ-and TNF-α+IFN-γ-induced apoptosis in MIN6 cells and human islets [16,17].…”

Section: Discussionmentioning

confidence: 99%

“…Neutralisation of IL-17A prevents diabetes in NOD mice when started at 10 weeks of age [15]. Moreover, circulating IL-17 + and beta cell-specific autoreactive CD4 + cells are present in the circulation of type 1 diabetes patients at diagnosis [16,17] and are associated with diabetes in NOD mice [18]. Importantly, increased expression of IL-17A was detected in the islets of a recently diagnosed type 1 diabetic patient [17] and increased numbers of Th17 cells are present in pancreatic lymph nodes of patients with long-term type 1 diabetes [19].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, circulating IL-17 + and beta cell-specific autoreactive CD4 + cells are present in the circulation of type 1 diabetes patients at diagnosis [16,17] and are associated with diabetes in NOD mice [18]. Importantly, increased expression of IL-17A was detected in the islets of a recently diagnosed type 1 diabetic patient [17] and increased numbers of Th17 cells are present in pancreatic lymph nodes of patients with long-term type 1 diabetes [19]. IL-17A enhances IL-1β+IFN-γ-or TNF-α+IFN-γ-induced apoptosis in rodent and human beta cells [16,17,20] and IL-1β+IFN-γ upregulates the expression of the beta cell IL-17A receptor via the transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription (STAT) 1 [17].…”

Section: Introductionmentioning

confidence: 99%

“…IL-17A enhances IL-1β+IFN-γ-or TNF-α+IFN-γ-induced apoptosis in rodent and human beta cells [16,17,20] and IL-1β+IFN-γ upregulates the expression of the beta cell IL-17A receptor via the transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription (STAT) 1 [17]. This raises the possibility that beta cell apoptosis in type 1 diabetes is initially triggered by Th1 cells and macrophages through the production of IL-1β and IFN-γ, and by other mechanisms, these processes then being followed by the additional proapoptotic effects of IL-17A-secreting Th17 cells [17].…”

Section: Introductionmentioning

confidence: 99%

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IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

et al. 2013

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Aims/hypothesis Cytotoxic T cells and macrophages contribute to beta cell destruction in type 1 diabetes at least in part through the production of cytokines such as IL-1β, IFN-γ and TNF-α. We have recently shown the IL-17 pathway to be activated in circulating T cells and pancreatic islets of type 1 diabetes patients. Here, we studied whether IL-17A upregulates the production of chemokines by human pancreatic islets, thus contributing to the build-up of insulitis. Methods Human islets (from 18 donors), INS-1E cells and islets from wild-type and Stat1 knockout mice were studied. Dispersed islet cells were left untreated, or were treated with IL-17A alone or together with IL-1β+IFN-γ or TNF-α+IFN-γ.RNA interference was used to knock down signal transducer and activator of transcription 1 (STAT1). Chemokine expression was assessed by quantitative RT-PCR, ELISA and histology. Cell viability was evaluated with nuclear dyes. Results IL-17A augmented IL-1β+IFN-γ-and TNF-α+IFN-γ-induced chemokine mRNA and protein expression, and apoptosis in human islets. Beta cells were at least in part the source of chemokine production. Knockdown of STAT1 in human islets prevented cytokine-or IL-17A+cytokine-induced apoptosis and the expression of particular chemokines, e.g. chemokine (C-X-C motif) ligands 9 and 10. Similar observations were made in islets isolated from Stat1 knockout mice. Conclusions/interpretation Our findings indicate that IL-17A exacerbates proinflammatory chemokine expression and secretion by human islets exposed to cytokines. This suggests that IL-17A contributes to the pathogenesis of type 1 diabetes by two mechanisms, namely the exacerbation of beta cell apoptosis and increased local production of chemokines, thus potentially aggravating insulitis.

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Section: Il-17a Exacerbates Cytokine-induced Apoptosis In Rat Ins-1e supporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

et al. 2013

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Hydrogen‐Bonded Multilayers of Tannic Acid as Mediators of T‐Cell Immunity

Kozlovskaya

Xue

Lei

et al. 2014

Adv Healthcare Materials

100

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Type 1 diabetes is an autoimmune-mediated disease resulting in the destruction of insulin-secreting pancreatic β-cells. Transplantation of insulin-producing islets is a viable treatment to restore euglycemia in Type 1 diabetics, however, the clinical application remains limited due to the use of toxic immunosuppressive therapies to prevent immune-mediated rejection. We present a nanothin polymer material with dual antioxidant and immunosuppressive properties capable of modulating both innate and adaptive immune responses crucial for transplantation outcome. Through the use of hollow microparticles (capsules) comprising of hydrogen-bonded multilayers of natural polyphenol (tannic acid) with poly(N-vinylpyrrolidone) (TA/PVPON) and with poly(N-vinylcaprolactam) (TA/PVCL), pro-inflammatory reactive oxygen and nitrogen species are efficiently dissipated and the production of IFN-γ and TNF-α pro-inflammatory cytokines are attenuated by cognate antigen-stimulated autoreactive CD4+ T cells. Our results provide evidence that TA-containing capsules are efficacious in immunomodulation and may provide physical transplant protection and prevent diabetogenic autoreactive T cell responses. Future studies will determine if xeno- and allotransplantation with (TA/PVPON)- or (TA/PVCL)-coated pancreatic islets will decrease the risk of graft rejection due to attenuation of oxidative stress and IFN-γ, and restore euglycemia in Type 1 diabetics.

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Combined Etanercept, GAD‐alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes

Ludvigsson

Routray

Vigård

et al. 2021

Diabetes Metabolism Res

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Aim:We aimed to study the feasibility and tolerability of a combination therapy consisting of glutamic acid decarboxylase (GAD-alum), Etanercept and vitamin D in children and adolescents with newly diagnosed with type 1 diabetes (T1D), and evaluate preservation of beta cell function. Material and Methods: Etanercept Diamyd Combination Regimen is an openlabelled multi-centre study pilot trial which enrolled 20 GAD antibodies positive T1D patients (7 girls and 13 boys), aged (mean ±SD): 12.4 ± 2.3 (8.3-16.1) years, with a diabetes duration of 81.4 ± 22.1 days. Baseline fasting C-peptide was 0.24 ± 0.1 (0.10-0.35) nmol/l. The patients received Day 1-450 Vitamin D (Calciferol) 2000 U/d per os, Etanercept sc Day 1-90 0.8 mg/kg once a week and GAD-alum sc injections (20 μg, Diamyd™) Day 30 and 60. They were followed for 30 months. Results: No treatment related serious adverse events were observed. After 6 months 90-min stimulated C-peptide had improved in 8/20 patients and C-peptideThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Peripheral and Islet Interleukin-17 Pathway Activation Characterizes Human Autoimmune Diabetes and Promotes Cytokine-Mediated β-Cell Death

Cited by 189 publications

References 37 publications

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

Hydrogen‐Bonded Multilayers of Tannic Acid as Mediators of T‐Cell Immunity

Combined Etanercept, GAD‐alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes

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