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PMID: 20835230 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes.

Nature immunology ·Vol. 11 ·No. 10 ·2010-10-00 ·Pages 897-904

Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, Mullooly N, Mielke LA, Harris J, Coll RC, Mills KH, Mok KH, Newsholme P, Nuñez G, Yodoi J, Kahn SE, Lavelle EC, O'Neill LA

Abstract

Interleukin 1β (IL-1β) is an important inflammatory mediator of type 2 diabetes. Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1β. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first required priming, a process that involved glucose metabolism and was facilitated by minimally oxidized low-density lipoprotein. Finally, mice transgenic for human IAPP had more IL-1β in pancreatic islets, which localized together with amyloid and macrophages. Our findings identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP.

MeSH Terms
Amyloid/metabolism Animals Carrier Proteins/antagonists & inhibitors,genetics,metabolism Cells, Cultured Dendritic Cells/immunology,metabolism Diabetes Mellitus, Type 2/immunology,metabolism Glyburide/pharmacology Humans Hypoglycemic Agents/pharmacology Interleukin-1beta/metabolism Islet Amyloid Polypeptide Islets of Langerhans/metabolism Macrophages/immunology,metabolism Mice Mice, Inbred C57BL Mice, Transgenic NLR Family, Pyrin Domain-Containing 3 Protein Rats Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors,genetics,metabolism
Chemicals
Amyloid Carrier Proteins Hypoglycemic Agents Interleukin-1beta Islet Amyloid Polypeptide NLR Family, Pyrin Domain-Containing 3 Protein NLRP3 protein, human Nlrp3 protein, rat Receptors, Cytoplasmic and Nuclear Glyburide
Authors & Affiliations
22 authors, click to expand affiliations / ORCID
Masters Seth L
Immunology Research Centre, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. [email protected]
Dunne Aisling
Subramanian Shoba L
Hull Rebecca L
Tannahill Gillian M
Sharp Fiona A
Becker Christine
Franchi Luigi
Yoshihara Eiji
Chen Zhe
Mullooly Niamh
Mielke Lisa A
Harris James
Coll Rebecca C
Mills Kingston H G
Mok K Hun
Newsholme Philip
Nuñez Gabriel
Yodoi Junji
Kahn Steven E
Lavelle Ed C
O'Neill Luke A J
References (51)
51 references, click to expand
  1. Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells.
    Proc Natl Acad Sci U S A. 1987 Jun;84(11):3881-5 PMID: 3035556
  2. Amyloid beta and amylin fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia.
    J Neurochem. 2000 Mar;74(3):1017-25 PMID: 10693932
  3. Amyloid formation results in recurrence of hyperglycaemia following transplantation of human IAPP transgenic mouse islets.
    Diabetologia. 2009 Jan;52(1):145-53 PMID: 19002432
  4. Islet amyloid polypeptide (IAPP) transgenic rodents as models for type 2 diabetes.
    ILAR J. 2006;47(3):225-33 PMID: 16804197
  5. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients.
    Proc Natl Acad Sci U S A. 1987 Dec;84(23):8628-32 PMID: 3317417
  6. Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation.
    J Clin Endocrinol Metab. 2008 Oct;93(10):4065-74 PMID: 18664535
  7. Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells.
    J Biol Chem. 2003 Jan 17;278(3):1561-8 PMID: 12424240
  8. Effects of pharmacological inhibition of NADPH oxidase or iNOS on pro-inflammatory cytokine, palmitic acid or H2O2-induced mouse islet or clonal pancreatic β-cell dysfunction.
    Biosci Rep. 2010 Dec;30(6):445-53 PMID: 20178457
  9. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization.
    Nat Immunol. 2008 Aug;9(8):847-56 PMID: 18604214
  10. Human amylin stimulates inflammatory cytokine secretion from human glioma cells.
    Neuroimmunomodulation. 2000;7(3):147-52 PMID: 10754402
  11. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles.
    Diabetes. 1999 Mar;48(3):491-8 PMID: 10078548
  12. Reactive oxygen species-independent activation of the IL-1beta inflammasome in cells from patients with chronic granulomatous disease.
    Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3030-3 PMID: 20133696
  13. Widespread amyloid deposition in transplanted human pancreatic islets.
    N Engl J Med. 2008 Aug 28;359(9):977-9 PMID: 18753660
  14. Gout-associated uric acid crystals activate the NALP3 inflammasome.
    Nature. 2006 Mar 9;440(7081):237-41 PMID: 16407889
  15. Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes.
    Diabetes. 2004 Jun;53(6):1509-16 PMID: 15161755
  16. Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2-deoxy-D-glucose during metabolic syndrome in obese JCR: LA-cp rats.
    Br J Pharmacol. 2007 May;151(2):216-25 PMID: 17375078
  17. Human high-density lipoprotein particles prevent activation of the JNK pathway induced by human oxidised low-density lipoprotein particles in pancreatic beta cells.
    Diabetologia. 2007 Jun;50(6):1304-14 PMID: 17437081
  18. TLR4 links innate immunity and fatty acid-induced insulin resistance.
    J Clin Invest. 2006 Nov;116(11):3015-25 PMID: 17053832
  19. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta.
    Nat Immunol. 2008 Aug;9(8):857-65 PMID: 18604209
  20. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets.
    J Clin Invest. 2002 Sep;110(6):851-60 PMID: 12235117
  21. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus.
    Nature. 1994 Apr 21;368(6473):756-60 PMID: 8152488
  22. Thioredoxin-interacting protein links oxidative stress to inflammasome activation.
    Nat Immunol. 2010 Feb;11(2):136-40 PMID: 20023662
  23. Active caspase-1 is a regulator of unconventional protein secretion.
    Cell. 2008 Mar 7;132(5):818-31 PMID: 18329368
  24. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome.
    J Cell Biol. 2009 Oct 5;187(1):61-70 PMID: 19805629
  25. Increased electronegative charge of serum low-density lipoprotein in patients with diabetes mellitus.
    Clin Chim Acta. 2004 Feb;340(1-2):93-8 PMID: 14734200
  26. Pharmacological discrimination of calcitonin receptor: receptor activity-modifying protein complexes.
    Mol Pharmacol. 2005 May;67(5):1655-65 PMID: 15692146
  27. Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide.
    Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3492-6 PMID: 8622964
  28. Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid.
    Diabetes. 2003 Sep;52(9):2304-14 PMID: 12941770
  29. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.
    Nature. 2010 Apr 29;464(7293):1357-61 PMID: 20428172
  30. Interleukin-1beta secretion is impaired by inhibitors of the Atp binding cassette transporter, ABC1.
    Blood. 1997 Oct 15;90(8):2911-5 PMID: 9376570
  31. Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide.
    Amyloid. 2001 Dec;8(4):242-9 PMID: 11791616
  32. Increased dietary fat promotes islet amyloid formation and beta-cell secretory dysfunction in a transgenic mouse model of islet amyloid.
    Diabetes. 2003 Feb;52(2):372-9 PMID: 12540610
  33. Oxidative stress is induced by islet amyloid formation and time-dependently mediates amyloid-induced beta cell apoptosis.
    Diabetologia. 2009 Apr;52(4):626-35 PMID: 19148619
  34. Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets?
    Diabetes. 2005 Nov;54(11):3238-44 PMID: 16249450
  35. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.
    Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7283-8 PMID: 8692984
  36. Interleukin-1-receptor antagonist in type 2 diabetes mellitus.
    N Engl J Med. 2007 Apr 12;356(15):1517-26 PMID: 17429083
  37. Toxic oligomers and islet beta cell death: guilty by association or convicted by circumstantial evidence?
    Diabetologia. 2010 Jun;53(6):1046-56 PMID: 20182863
  38. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans.
    Science. 1986 Jun 20;232(4757):1545-7 PMID: 3086977
  39. Mechanisms linking obesity to insulin resistance and type 2 diabetes.
    Nature. 2006 Dec 14;444(7121):840-6 PMID: 17167471
  40. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes.
    Diabetes Res. 1988 Dec;9(4):151-9 PMID: 3073901
  41. Rapid deposition of amyloid in human islets transplanted into nude mice.
    Diabetologia. 1995 May;38(5):543-9 PMID: 7489836
  42. Fibrillar islet amyloid polypeptide (amylin) is internalised by macrophages but resists proteolytic degradation.
    Cell Tissue Res. 1998 Feb;291(2):285-94 PMID: 9426315
  43. Longitudinal studies on the development of diabetes in individual Macaca nigra.
    Diabetologia. 1986 May;29(5):301-6 PMID: 3522329
  44. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
    J Immunol. 2009 Jul 15;183(2):787-91 PMID: 19570822
  45. Macrophages and pancreatic islet amyloidosis.
    Amyloid. 1998 Dec;5(4):247-54 PMID: 10036582
  46. Association between oxidized LDL, obesity and type 2 diabetes in a population-based cohort, the Health, Aging and Body Composition Study.
    Diabetes Metab Res Rev. 2009 Nov;25(8):733-9 PMID: 19780064
  47. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica.
    Science. 2008 May 2;320(5876):674-7 PMID: 18403674
  48. Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.
    Proc Natl Acad Sci U S A. 2009 Jan 20;106(3):870-5 PMID: 19139407
  49. Techniques to study amyloid fibril formation in vitro.
    Methods. 2004 Sep;34(1):151-60 PMID: 15283924
  50. S20G mutation of the amylin gene is associated with Type II diabetes in Japanese. Study Group of Comprehensive Analysis of Genetic Factors in Diabetes Mellitus.
    Diabetologia. 2001 Jul;44(7):906-9 PMID: 11508277
  51. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.
    Diabetes. 2003 Mar;52(3):812-7 PMID: 12606524
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1935
Email
[email protected]
Published
2010-10-00
Epub
2010-00-12
Pages
897-904
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC3103663
Subset
IM
Grants
NIAID NIH HHS · R56 AI063331 · United States
NIDDK NIH HHS · R01 DK075998-03 · United States
NIDDK NIH HHS · DK-75998 · United States
NIAID NIH HHS · R01 AI063331 · United States
NIAID NIH HHS · AI063331 · United States
NIDDK NIH HHS · R01 DK075998 · United States
Corrections
CommentIn
PMID: 20856216
CommentIn
PMID: 21035753
CommentIn
PMID: 21080610
External Links
PubMed source DOI: 10.1038/ni.1935 PMC Full Text View journal details
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