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

doi:10.1038/nm.3265

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 journal › Article › peer-review

331 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 language	English
Pages (from-to)	1132-1140
Number of pages	9
Journal	Nature Medicine
Volume	19
Issue number	9
DOIs	https://doi.org/10.1038/nm.3265
State	Published - Sep 2013
Externally published	Yes

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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Jourdan, T., Godlewski, G., Cinar, R., Bertola, A., Szanda, G., Liu, J., Tam, J., Han, T., Mukhopadhyay, B., Skarulis, M. C., Ju, C., Aouadi, M., Czech, M. P., & Kunos, G. (2013). Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nature Medicine, 19(9), 1132-1140. https://doi.org/10.1038/nm.3265

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title = "Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes",

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.",

author = "Tony Jourdan and Grzegorz Godlewski and Resat Cinar and Adeline Bertola and Gergo Szanda and Jie Liu and Joseph Tam and Tiffany Han and Bani Mukhopadhyay and Skarulis, {Monica C.} and Cynthia Ju and Myriam Aouadi and Czech, {Michael P.} and George Kunos",

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.{\textquoteright}s laboratory was supported by grants from the NIH (DK085753 and AI046629).",

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doi = "10.1038/nm.3265",

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AU - Jourdan, Tony

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AU - Bertola, Adeline

AU - Szanda, Gergo

AU - Liu, Jie

AU - Tam, Joseph

AU - Han, Tiffany

AU - Mukhopadhyay, Bani

AU - Skarulis, Monica C.

AU - Ju, Cynthia

AU - Aouadi, Myriam

AU - Czech, Michael P.

AU - Kunos, George

N1 - 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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N2 - 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.

AB - 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.

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Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes

Abstract

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