Activation of the Nlrp3 Inflammasome in Infiltrating Macrophages by Endocannabinoids Mediates Beta Cell Loss in Type 2 Diabetes

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2013 Aug 20

PMID 23955712

Citations 216

Authors

Tony Jourdan

Grzegorz Godlewski

Resat Cinar

Adeline Bertola

Gergo Szanda

Jie Liu

Joseph Tam

Tiffany Han

Bani Mukhopadhyay

Monica C Skarulis

Cynthia Ju

Myriam Aouadi

Michael P Czech

George Kunos

Affiliations

Soon will be listed here.

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.

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