Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.
Tony Jourdan,Grzegorz Godlewski,Resat Cinar,Adeline Bertola,Gergő Szanda,Jie Liu,Joseph Tam,Tiffany Han,Bani Mukhopadhyay,Monica C. Skarulis,Cynthia Ju,Myriam Aouadi,Michael P. Czech,George Kunos +13 more
TLDR
It is shown that beta cell failure in adult ZDF rats is not associated with CB1R signaling in beta cells, but rather in M1 macrophage infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages.Abstract:
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.read more
Citations
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Inflammasomes: mechanism of action, role in disease, and therapeutics
TL;DR: Increasing evidence in mouse models strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases.
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Mechanisms and Functions of Inflammasomes
Mohamed Lamkanfi,Vishva M. Dixit +1 more
TL;DR: This Review summarizes recent insights into inflammasome biology and discusses the questions that remain in the field.
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Targeting inflammation in the treatment of type 2 diabetes: time to start
TL;DR: Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.
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The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives.
Sotirios Tsalamandris,Alexios S. Antonopoulos,Evangelos Oikonomou,George-Aggelos Papamikroulis,Georgia Vogiatzi,Spyridon Papaioannou,Spyros Deftereos,Dimitris Tousoulis +7 more
TL;DR: In this article, the role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease.
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Endocannabinoid signaling at the periphery: 50 years after THC
Mauro Maccarrone,Itai Bab,Tamás Bíró,Guy A. Cabral,Sudhansu K. Dey,Vincenzo Di Marzo,Justin C. Konje,George Kunos,Raphael Mechoulam,Pal Pacher,Keith A. Sharkey,Andreas Zimmer +11 more
TL;DR: The state of the art of critical eCB functions in peripheral organs is reviewed to establish consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes.
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