Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes
- 18 August 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 19 (9), 1132-1140
- https://doi.org/10.1038/nm.3265
Abstract
George Kunos and his colleagues show in a rat model that endocannabinoid activation of the Nlrp3 inflammasome in macrophages results in death of pancreatic beta cells, and thus development of type 2 diabetes mellitus. These results suggest that preventing this process might be a therapeutic option for diabetes in the clinic. 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.Keywords
This publication has 71 references indexed in Scilit:
- Thioredoxin-Interacting Protein Mediates ER Stress-Induced β Cell Death through Initiation of the InflammasomeCell Metabolism, 2012
- Hepatic Cannabinoid Receptor-1 Mediates Diet-Induced Insulin Resistance via Inhibition of Insulin Signaling and Clearance in MiceGastroenterology, 2012
- Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB 1 ) receptors in the regenerating liverProceedings of the National Academy of Sciences of the United States of America, 2011
- The Inflammasome-Mediated Caspase-1 Activation Controls Adipocyte Differentiation and Insulin SensitivityCell Metabolism, 2010
- Inhibitor of Fatty Acid Amide Hydrolase Normalizes Cardiovascular Function in Hypertension without Adverse Metabolic EffectsCell Chemical Biology, 2010
- Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetesNature Immunology, 2010
- Transcriptional Regulation of Cannabinoid Receptor-1 Expression in the Liver by Retinoic Acid Acting via Retinoic Acid Receptor-γOnline Journal of Public Health Informatics, 2010
- The InflammasomesCell, 2010
- Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammationNature, 2009
- The future of endocannabinoid-oriented clinical research after CB1 antagonistsPsychopharmacology, 2009