Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling

Wen, Haitao; Gris, Denis; Lei, Yu; Jha, Sushmita; Zhang, Lu; Huang, Max; Brickey, W. June; Ting, Jenny P.Y.

doi:10.1038/ni.2022

Cited by 1,538 publications

(1,576 citation statements)

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“…Deregulated NLRP3 inflammasome activation is associated with multiple diseases such as gout, Crohn's disease, atherosclerosis, and type II diabetes (Martinon et al, 2006;Duewell et al, 2010;Zaki et al, 2010;Wen et al, 2011). However, the mechanism of NLRP3 infl ammasome activation and its exact localization in the cell remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Cellular localization of NLRP3 inflammasome

et al. 2013

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Infl ammasome is a large protein complex activated upon cellular stress or microbial infection, which triggers maturation of pro-inflammatory cytokines interleukin-1β and interleukin-18 through caspase-1 activation. Nod-like receptor family protein 3 (NLRP3) is the most characterized infl ammasome activated by various stimuli. However, the mechanism of its activation is unclear and its exact cellular localization is still unknown. We examined the potential co-localization of NLRP3 infl ammasome with mitochondria and seven other organelles under adenosine triphosphate, nigericin or monosodium urate stimulation in mouse peritoneal macrophages using confocal microscopy approach. Our results revealed that the activated endogenous apoptosis-associated speck-like protein containing a CARD (ASC) pyroptosome forms in the cytoplasm and co-localizes with NLRP3 and caspase-1, but not with any of the organelles screened. This study indicates that the ASC pyroptosome universally localizes within the cytoplasm rather than with any specifi c organelles.

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Section: Discussionmentioning

confidence: 99%

Cellular localization of NLRP3 inflammasome

et al. 2013

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“…The deleterious effects of visceral adipose tissue might be also related to an up-regulated expression and activation of NLRP3 inflammasome compared to subcutaneous adipose tissue in overweight and obese patients [33,57]. The NLRP3 inflammasome seems to act as a sensor of metabolic danger signals that accumulate during obesity, including high levels of glucose [52], saturated free fatty acids [58,59], lipid intermediates such as ceramides [56] and uric acid [51], and its activation results in IL-1β production and induction of numerous cytokines and chemokines.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…A c c e p t e d M a n u s c r i p t 11 through the activation of NLRP3 inflammasome [58] whereas unsaturated fatty acids exert strong anti-inflammatory effects resulting in improved insulin sensitivity in obese and T2DM…”

Section: Page 11 Of 24mentioning

confidence: 99%

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Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

Esser

Legrand-Poels

Piette

et al. 2014

Diabetes Research and Clinical Practice

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:It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammarory therapies could have a place in prevention and treatment of type 2 diabetes.

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“…The NLRP3 inflammasome senses lipotoxicity-induced increases in intracellular ceramide associated with caspase-1 cleavage in ATM, and Nlrp3 -/-mice are prevented from insulin resistance and inflammasome activation in liver and adipose tissues 98 . Saturated fatty acids, such as palmitate, but not unsaturated oleate, induces activation of the NLRP3-ASC inflammasome causing caspase-1, IL1β, and IL18 production and reduced insulin tolerance and sensitivity 99 . In pancreatic islet cells, islet amyloid polypeptide also triggers the NLRP3 inflammasome and generation of mature IL1β, which is reversed by treatment with glyburide 100 .…”

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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Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling

Cited by 1,538 publications

References 51 publications

Cellular localization of NLRP3 inflammasome

Cellular localization of NLRP3 inflammasome

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

Innate immunity in diabetes and diabetic nephropathy

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