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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

319 Scopus citations

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 languageAmerican English
Pages (from-to)1132-1140
Number of pages9
JournalNature Medicine
Volume19
Issue number9
DOIs
StatePublished - Sep 2013
Externally publishedYes

Bibliographical note

Funding Information:
We thank J.F. McElroy and R.J. Chorvat (Jenrin Discovery) for providing the CB1R antagonist JD5037 and its inactive diastereomer, O. Gavrilova (NIDDK, US National Institutes of Health (NIH)) for advice on pancreatic islet isolation, J. Harvey-White for technical assistance, D. Feng for FACS analyses, R. Kechrid for assistance with the animal studies and P. Staker for collecting human blood specimens. This study was supported by intramural NIH funds. The work from M.P.C.’s laboratory was supported by grants from the NIH (DK085753 and AI046629).

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