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

Jourdan, Tony; Godlewski, Grzegorz; Çınar, Reşat; Bertola, Adeline; Szanda, Gergö; Liu, Jie; Tam, Joseph; Han, Tiffany; Mukhopadhyay, Bani; Skarulis, Monica C.; Ju, Cynthia; Aouadi, Myriam; Czech, Michael P.; Kunos, George

doi:10.1038/nm.3265

Cited by 355 publications

(362 citation statements)

References 71 publications

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“…Although important, sympathetic ligands alone likely do not explain all the PTX-sensitive inhibition of β-cell proliferation, and other Gi-GPCRs, such as Cnr1, along with non-cell-autonomous effects of Gα i/o signaling, surely contribute as well (24,(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Berger

Scheel

Macias

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs—including the α-2a adrenergic receptor, ADRA2A—increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

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Section: Discussionmentioning

confidence: 99%

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Berger

Scheel

Macias

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The NLRP3 inflammasome, TLR2, and TLR4 are triggers for islet inflammation in T2DM and the activation of macrophages in various tissues is also mediated by activation of the NLRP3 inflammasome 102 . Pancreatic β-cell failure in the Zucker diabetic fatty rat is associated with activation of NLRP3-ASC infammasome in M1 macrophages infiltrating into pancreatic islets 103 . Furthermore, adipose S100A8 and S100A9 induces ATM to provoke TLR4/MyD88 and NLRP3 inflammasome-dependent IL1β production and stimulates IL1 receptors on bone marrow myeloid progenitors to contribute to the prominent monocytosis and neutrophilia observed in obesity 80 .…”

Section: [H3] Nod2mentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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“…Increasing evidence indicates that the NLRP3 inflammasome plays an important role in obesity and type 2 diabetes (12)(13)(14). However, little is known about the role of NLRP3 in autoimmune diabetes.…”

mentioning

confidence: 99%

NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets

Ding

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

116

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Studies in animal models and human subjects have shown that both innate and adaptive immunity contribute to the pathogenesis of type 1 diabetes (T1D). Whereas the role of TLR signaling pathways in T1D has been extensively studied, the contribution of the nucleotidebinding oligomerization domain, leucine-rich repeat and pyrin domaincontaining protein (NLRP) 3 inflammasome pathway remains to be explored. In this study, we report that NLRP3 plays an important role in the development of T1D in the nonobese diabetic (NOD) mouse model. NLRP3 deficiency not only affected T-cell activation and Th1 differentiation, but also modulated pathogenic T-cell migration to the pancreatic islet. The presence of NLRP3 is critical for the expression of the chemokine receptors CCR5 and CXCR3 on T cells. More importantly, NLRP3 ablation reduced the expression of chemokine genes CCL5 and CXCL10 on pancreatic islet cells in an IRF-1-dependent manner. Our results suggest that molecules involved in chemotaxis, accompanied by the activation of the NLRP3 inflammasome, may be effective targets for the treatment of T1D.NLRP3 | islet | type 1 diabetes | chemokine | NOD mouse

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

Cited by 355 publications

References 71 publications

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Innate immunity in diabetes and diabetic nephropathy

NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets

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

Cited by 355 publications

References 71 publications

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Innate immunity in diabetes and diabetic nephropathy

NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets

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Product

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Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion

Gα _i/o -coupled receptor signaling restricts pancreatic β-cell expansion