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, G. Szanda, Jie Liu, Joseph Tam, Tiffany Han, Bani Mukhopadhyay, Monica C. Skarulis, Cynthia Ju, Myriam Aouadi, Michael P. Czech, George Kunos

Research output: Contribution to journalArticle

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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 CB 1 R-deficient (Cnr1-/-) or Nlrp3-/- mice, with the endocannabinoid anandamide. Peripheral CB1R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB 1R 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.

Original languageEnglish
Pages (from-to)1132-1140
Number of pages9
JournalNature Medicine
Volume19
Issue number9
DOIs
Publication statusPublished - Sep 2013

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Inflammasomes
Endocannabinoids
Macrophages
Medical problems
Type 2 Diabetes Mellitus
Chemical activation
Cannabinoid Receptor CB1
Insulin
Insulin Resistance
Rats
Islets of Langerhans
Hyperglycemia
Rodentia
Obesity
Glucose

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. / Jourdan, Tony; Godlewski, Grzegorz; Cinar, Resat; Bertola, Adeline; Szanda, G.; Liu, Jie; Tam, Joseph; Han, Tiffany; Mukhopadhyay, Bani; Skarulis, Monica C.; Ju, Cynthia; Aouadi, Myriam; Czech, Michael P.; Kunos, George.

In: Nature Medicine, Vol. 19, No. 9, 09.2013, p. 1132-1140.

Research output: Contribution to journalArticle

Jourdan, T, Godlewski, G, Cinar, R, Bertola, A, Szanda, G, Liu, J, Tam, J, Han, T, Mukhopadhyay, B, Skarulis, MC, Ju, C, Aouadi, M, Czech, MP & Kunos, G 2013, 'Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes', Nature Medicine, vol. 19, no. 9, pp. 1132-1140. https://doi.org/10.1038/nm.3265
Jourdan, Tony ; Godlewski, Grzegorz ; Cinar, Resat ; Bertola, Adeline ; Szanda, G. ; Liu, Jie ; Tam, Joseph ; Han, Tiffany ; Mukhopadhyay, Bani ; Skarulis, Monica C. ; Ju, Cynthia ; Aouadi, Myriam ; Czech, Michael P. ; Kunos, George. / Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. In: Nature Medicine. 2013 ; Vol. 19, No. 9. pp. 1132-1140.
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