Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes

Masters, Seth L.; Dunne, Aisling; Subramanian, Shoba L.; Hull, Rebecca L.; Tannahill, Gillian M.; Sharp, Fiona A.; Becker, Christine; Franchi, Luigi; Yoshihara, Eiji; Chen, Zhe; Mullooly, N; Mielke, Lisa A.; Harris, James; Coll, Rebecca C.; Mills, Kingston H. G.; Mok, K. Hun; Newsholme, Philip; Núñez, Gabriel; Yodoi, Junji; Kahn, Steven E.; Lavelle, Ed C.; O’Neill, Luke A. J.

doi:10.1038/ni.1935

Cited by 1,198 publications

(1,071 citation statements)

References 52 publications

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“…Moreover, islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas, seems to contribute to IL-1β production in islets through activation of the NLRP3 inflammasome [54].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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

Esser

Legrand-Poels

Piette

et al. 2014

Diabetes Research and Clinical Practice

1,621

1,064

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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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Section: Accepted Manuscriptmentioning

confidence: 99%

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

Esser

Legrand-Poels

Piette

et al. 2014

Diabetes Research and Clinical Practice

1,621

1,064

View full text Add to dashboard Cite

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“…For example, inflammasomemediated IL-1b overproduction is involved in the pathogenesis of type 2 diabetes, liver damage and muscular dystrophy. [132][133][134] Inflammasome-mediated processes were also observed in cancer, but the association between the inflammasome/IL-1b axis and cancer development is ambiguous. In some studies the inflammasome seems to promote inflammation-mediated tumor development, also confirmed in lung mesotheliomas caused by silica and asbestos.…”

Section: Adaptive Immunity-mediated Diseasesmentioning

confidence: 99%

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

2011

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Nucleotide-binding oligomerization domain (NOD)-containing protein-like receptors (NLRs) are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition. Some NLRs form the framework for cytosolic platforms called inflammasomes, which orchestrate the early inflammatory process via IL-1b activation. Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases. Moreover, the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis. In this review, we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders.

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“…In primed dendritic cells, IAPP oligomers can activate the NLRP3 inflammasome leading to production of IL-1 [93]. IL-1 secretion was significantly decreased with exposure to inhibitors of caspase-1, glucose metabolism and lysosomal acidification.…”

Section: Proteotoxic Stress In the Pathogenesis Of Diseases Not Formementioning

confidence: 99%

“…IL-1 secretion was significantly decreased with exposure to inhibitors of caspase-1, glucose metabolism and lysosomal acidification. Glyburide, a sulfonylurea used in T2DM treatment, also inhibited IL-1 production [93]. Soluble IAPP oligomers, and not the higher order fibrils, appear to be critical for IL-1production.…”

Section: Proteotoxic Stress In the Pathogenesis Of Diseases Not Formementioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes

Cited by 1,198 publications

References 52 publications

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

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

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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