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Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes
Open accessAbstract
Interleukin 1β (IL-1β) is an important inflammatory mediator of type 2 diabetes. Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1β. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first required priming, a process that involved glucose metabolism and was facilitated by minimally oxidized low-density lipoprotein. Finally, mice transgenic for human IAPP had more IL-1β in pancreatic islets, which localized together with amyloid and macrophages. Our findings identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP.
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“that induce interleukin (IL)-1β release to recruit macrophages and enhance local islet inflammation ( 45 ).”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [45]
Experimental — accuracy not yet measuredIn the citing paper
“A potential role for NLRP3 in promoting elevated levels of IL-1β in type 2 diabetes was also implied by the observation of NLRP3-dependent IL-1β secretion by mouse bone marrow-derived macrophages and dendritic cells in response to islet amyloid polypeptide (IAPP), which is deposited in the pancreas and associated with loss of β-cell function in type 2 diabetes61.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [61]
In the citing paper
“Interestingly, the anti-diabetic drug glyburide (Glibenclamide; Roche/Sanofi-Aventis) has been shown to block glucose-mediated secretion of IL-1β by mouse pancreatic islets62, as well as IL-1β production by macrophages in response to IAPP61, and NLRP3-deficient mice were more glucose tolerant than wild-type mice62.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [61]
In the citing paper
“In a separate study, no differences in IL-1β secretion were observed between wild-type and TXNIP-deficient bone marrow-derived macrophages in response to several NLRP3 stimuli, including MSU crystals and ATP61.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [61]
In the citing paper
“However, the role of TXNIP and ROS in NLRP3 activation has been challenged.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [61]
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Islet Amyloid Polypeptide Is a Target Antigen for Diabetogenic CD4+ T Cells
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NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction
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Pyroptotic death storms and cytopenia
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“Common multifactorial conditions such as atherosclerosis [319], type II diabetes [320], aging [321], and obesity [322] may also feature an autoinflammatory component, and new syndromes falling within the ‘autoinflammatory’ spectrum are likely to be identified as our understanding of innate immunity continues to improv…”
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“Further evidence from other researchers has indicated that release of CTSB after lysosomal damage can activate NLRP3, consistent with our results (27).”
ResultDeletion of Fas protects islet beta cells from cytotoxic effects of human islet amyloid polypeptide
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“For example, monosodium urate (MSU), calcium pyrophosphate dihydrate (CPPD) (41), cholesterol crystals (42), amyloid β (80), fatty acids (47), and mtDNA (48) have all been reported to activate NLRP3.”
BackgroundDeath and Dysfunction of Transplanted β-Cells: Lessons Learned From Type 2 Diabetes?
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“IAPP aggregates, which form rapidly in transplanted islets, promote proinflammatory cytokine and chemokine release by macrophages, dendritic cells, and islets in vitro (7,43), an effect that is amplified by interleukin-1 (IL-1) signaling.”
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Antidiabetic drug glyburide modulates depressive-like behavior comorbid with insulin resistance
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“[66] doubted the role of TXNIP in altering the effect of glyburide on the inflammasome.”
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“Understanding the influence of different cellular factors on hIAPP aggregation will provide more insight into the onset of T2DM and help to develop novel therapeutic strategies.”
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“Of note, neither form of hIAPP was able to induce IL-1 secretion after only 1 h of treatment, consistent with a mechanism for NLRP3 activation that requires more time than the response to ATP and may involve phagocytosis with subsequent lysosomal disruption (8, 9).”
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“Islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during T2DM, can activate nucleotide-binding and oligomerization domain (NACHT), leucine-rich repeat (LRR), and prin domain- (PYD-) containing protein 3 (NLRP3) in causing infiltrated macrophages, generating IL1β, and reducing β-ce…”
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“However, another report that compared P2X7R-dependent or NLRP3-inflammasome activation in macrophages from wild-type versus TXNIP-knockout mice failed to demonstrate a critical role for TXNIP (28).”
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Caspase-1 as a regulatory molecule of lipid metabolism
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“Some of these are uric acid crystals associated with Gout [17], extracellular adenosine triphosphate (ATP), calcium channel affecting marine toxin maitotoxin [18], ceramides [19], bacterial ribonucleic acid (RNA) [20], increased plasma free fatty acid [21, 22], high blood glucose level [23], and islet amyloid polypept…”
BackgroundEntrectinib inhibits NLRP3 inflammasome and inflammatory diseases by directly targeting NEK7
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NLRP3 inflammasome is expressed and regulated in human islets
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The Effects of Curcumin on Inflammasome: Latest Update
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“Normal activation of the NLRP3 inflammasome contributes to host defense, but abnormal activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease, and atherosclerosis [13].”
BackgroundReframing the link between metabolism and NLRP3 inflammasome: therapeutic opportunities
Ortega, M. A., León-Oliva, D. D., Montero, C. G., Fraile‐Μartinez, O., Boaru, D. L., de Castro, A. V., Sáez, M. A., López-González, L., Buján, J., Álvarez-Mon, M. Á., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1232629 · Cited by 58
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Unconventional Pathways of Secretion Contribute to Inflammation
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“NLRP3-dependent secretion of IL-1β is closely linked to numerous non-communicable diseases including haemorrhagic disorders [50,51], Alzheimer’s disease [52,53], gout [54], diabetes [55] and atherosclerosis [56].”
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“In this review, we explain the interactions between curcumin and amyloid conformations and the effective mechanisms in reducing Aβ, tau peptide, α-synuclein, IAPP, and other protein depositions in some neurodegenerative diseases and T2D.”
BackgroundInfluentialThe Complement Pathway: New Insights into Immunometabolic Signaling in Diabetic Kidney Disease
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“Inflammasome activation is a central element in the pathophysiology of a range of chronic diseases, including cryoporin-associated periodic syndromes, gout, inflammatory bowel diseases, liver fibrosis, and possibly also complications of diabetes (99, 154).”
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“Dysregulation of the NLRP3 inflammasome has been implicated in various inflammatory and autoimmune diseases [3], including gout [4], type 2 diabetes [5], rheumatoid arthritis [6], atherosclerosis [7], and Alzheimer disease [8].”
Inflammasome activation: from inflammatory disease to infection
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Self-citationActivation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure
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Autophagy as a crosstalk mediator of metabolic organs in regulation of energy metabolism
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Scropolioside B Inhibits IL-1βand Cytokines Expression through NF-κB and Inflammasome NLRP3 Pathways
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Regulated Cell Death Seen through the Lens of Islet Transplantation
Bruni, A. D. C., Bornstein, S. R., Linkermann, A., & Shapiro, A. M. J. (2018) · Cell Transplantation · doi:10.1177/0963689718766323 · Cited by 48
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Human IAPP amyloidogenic properties and pancreatic β-cell death
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Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor
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ER Stress-induced Inflammasome Activation Contributes to Hepatic Inflammation and Steatosis
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Thioredoxin-Interacting Protein in Cancer and Diabetes
Masutani, H. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0038 · Cited by 46
“Bone marrow (BM)-derived macrophages from Txnip-deficient mice, compared with wild-type mice, showed no difference in IL-1b secretion in response to islet amyloid polypeptide (IAPP) or other inflammasome activators (91).”
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“Activation of the NLRP3 inflammasome by islet amyloid polypeptide, responsible for the amyloid deposits that form in the pancreas during type 2 diabetes, results in the generation of mature IL-1 , which induces apoptosis in pancreatic beta cells (43).”
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Immune dysfunction in developmental programming of type 2 diabetes mellitus
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NLRP3 inflammasome activation, metabolic danger signals, and protein binding partners
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The Role of NLRP3 Inflammasome in Pneumococcal Infections
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“NLRP3 inflammasome signaling is implicated in the onset of a number of diseases, including gout (24), atherosclerosis (23), type ІІ diabetes (42, 43), Cryopyrin-associated periodic syndrome (CAPS) (44), various types of cancer (45), and inflammatory bowel disease (IBD) (46).”
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A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
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CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced β-Cell Apoptosis
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Metadata
- Authors
- Masters, S. L., Dunne, A., Subramanian, S. L., Hull, R. L., Tannahill, G. M., Sharp, F. A., Becker, C., Franchi, L., Yoshihara, E., Chen, Z., Mullooly, N., Mielke, L. A., Harris, J., Coll, R. C., Mills, K. H. G., Mok, K. H., Newsholme, P., Nuñez, G., Yodoi, J., Kahn, S. E., Lavelle, E. C., & O'Neill, L. A. J.
- Affiliations
- Trinity College Dublin (IE)
- University of Washington (US)
- University of Michigan (US)
- Kyoto University (JP)
- University College Dublin (IE)
- Corresponding author
- Masters, Seth L
- ORCID
- Venue
- Nature Immunology
- Published
- 2010-09-12
- Volume
- 11
- Issue
- 10
- Pages
- 897-904
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3103663
- OpenAlex
- W2034946303
- Cited by
- 1,330
- References
- 55
- Citations by year
- 2026: 58 · 2025: 57 · 2024: 64 · 2023: 75 · 2022: 71 · 2021: 99 · 2020: 100 · 2019: 95 · 2018: 82 · 2017: 83 · 2016: 73 · 2015: 101 · 2014: 95 · 2013: 112 · 2012: 83
- FWCI
- 35.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- eSpace (Curtin University) (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI063331, R56AI063331, R01AI063331, R37AI063331)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-75998, R01DK075998)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- NLRP3 inflammasome, amylin, IL-1β, type 2 diabetes, beta cell destruction, glibenclamide, LDL oxidation, glucose metabolism, inflammasome priming, pancreatic islets, macrophages, amyloid deposition
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Amyloid, Animals, Carrier Proteins, Cells, Cultured, Dendritic Cells, Diabetes Mellitus, Type 2, Glyburide, Humans, Hypoglycemic Agents, Islets of Langerhans, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Cytoplasmic and Nuclear, Mice, Rats, Interleukin-1beta, Islet Amyloid Polypeptide
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