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      High IL-1α Production Was Induced in the WBN/Kob- Lepr fa Type 2 Diabetes Mellitus Rat Model and Inhibited by Syphacia Muris Infection

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          Summary

          The novel WBN/Kob- Lepr fa ( fa/fa) congenic rat strain is considered a useful rat model of type 2 diabetes mellitus (T2DM). Accumulating findings suggest that low-grade inflammation is a causative factor in T2DM and that circulating levels of inflammatory cytokines are associated with insulin resistance. However, inflammatory cytokine profiles and their correlations with T2DM development/ progression in fa/fa rats have not been studied. In this study, we found that the fa/fa rats had considerably high plasma levels of interleukin (IL)-1α. Abundant cecal IL-1α mRNA expression and cecal inflammation with infiltrating IL-1α-producing macrophages was observed in fa/fa rats. Bone marrow derived macrophages from fa/fa rats expressed high levels of IL-1α upon lipopolysaccharide stimulation. Furthermore, Syphacia muris infection, which delays the onset of T2DM, reduced both plasma and cecal IL-1α levels in fa/fa rats. These results suggest that macrophage infiltration and IL-1α secretion comprise an important part of T2DM development and that S. muris infection inhibits pro-inflammatory cytokine expression in fa/fa rats.

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          Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets.

          Kathrin Maedler, Pavel Sergeev, Frederic Ris … (2002)
          In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.
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            Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.

            Tony Jourdan, Grzegorz Godlewski, Resat Cinar … (2013)
            Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB₁Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB₁R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB₁R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB₁R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB₁R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB₁R as a therapeutic target in T2DM.
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              Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis.

              Stefan Freigang, Franziska Ampenberger, Gisela Weiss … (2013)
              Chronic inflammation is a fundamental aspect of metabolic disorders such as obesity, diabetes and cardiovascular disease. Cholesterol crystals are metabolic signals that trigger sterile inflammation in atherosclerosis, presumably by activating inflammasomes for IL-1β production. We found here that atherogenesis was mediated by IL-1α and we identified fatty acids as potent inducers of IL-1α-driven vascular inflammation. Fatty acids selectively stimulated the release of IL-1α but not of IL-1β by uncoupling mitochondrial respiration. Fatty acid-induced mitochondrial uncoupling abrogated IL-1β secretion, which deviated the cholesterol crystal-elicited response toward selective production of IL-1α. Our findings delineate a previously unknown pathway for vascular immunopathology that links the cellular response to metabolic stress with innate inflammation, and suggest that IL-1α, not IL-1β, should be targeted in patients with cardiovascular disease.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Helminthologia
                Journal ID (iso-abbrev): Helminthologia
                Journal ID (publisher-id): helm
                Journal ID (pmc): helm
                Title: Helminthologia
                Publisher: Sciendo
                ISSN (Print): 0440-6605
                ISSN (Electronic): 1336-9083
                Publication date Collection: March 2018
                Publication date (Electronic): 27 January 2018
                Volume: 55
                Issue: 1
                Pages: 12-20
                Affiliations
                [1 ]Laboratory of Veterinary Immunology, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University , 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan
                [2 ]Laboratory of Parasitology, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University , 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan
                Author notes
                Article
                Publisher ID: helm-2017-0050
                DOI: 10.1515/helm-2017-0050
                PMC ID: 6799528
                SO-VID: fcc1eff9-76a3-401c-921c-162bf95521af
                Copyright © © 2018 M. Okamoto, R. Ito, K. Taira, T. Ikeda, published by Sciendo
                License:

                This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

                History
                Date received : 03 March 2017
                Date accepted : 05 September 2017
                Page count
                Pages: 9
                Categories
                Subject: Research Articles

                Keywords: il-1α,macrophage,syphacia muris,type 2 diabetes mellitus,wbn/kob-leprfa
                Data availability:
                Keywords: il-1α, macrophage, syphacia muris, type 2 diabetes mellitus, wbn/kob-leprfa

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