Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes.
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.
Masters
Seth L
SL
Immunology Research Centre, School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. smasters@tcd.ie
Dunne
Aisling
A
Subramanian
Shoba L
SL
Hull
Rebecca L
RL
Tannahill
Gillian M
GM
Sharp
Fiona A
FA
Becker
Christine
C
Franchi
Luigi
L
Yoshihara
Eiji
E
Chen
Zhe
Z
Mullooly
Niamh
N
Mielke
Lisa A
LA
Harris
James
J
Coll
Rebecca C
RC
Mills
Kingston H G
KH
Mok
K Hun
KH
Newsholme
Philip
P
Nuñez
Gabriel
G
Yodoi
Junji
J
Kahn
Steven E
SE
Lavelle
Ed C
EC
O'Neill
Luke A J
LA
D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D053583:Interleukin-1beta; D058228:Islet Amyloid Polypeptide; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C573346:Nlrp3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D005905:Glyburide