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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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Citations
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“Indeed, one recent study linked IAPP to production of pro-inflammatory 1L-1b by the NLRP3 inflammasome, a multiprotein complex that responds to internal danger signals (Masters et al. 2010).”
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“Pancreatic b-cells are continually depleted as type 2 diabetes progresses, which has been linked to the dysregulation of NLRP3 and production of IL-1b and, ultimately, pancreatic b-cell death (Masters et al., 2010).”
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Rojas, J., Bermúdez, V., Palmar, J., Martínez, M. S., Olivar, L. C., Nava, M., Tomey, D., Rojas, M., Salazar, J. J., Garicano, C., et al. (2018) · Journal of Diabetes Research · doi:10.1155/2018/9601801 · Cited by 189
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“However, these authors also failed to detect differences in IL-1b production upon stimulation with ATP and uric crystals in wild-type versus TXNIP macrophages (25).”
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“…toxicity support a role for extracellular oligomers, as do studies showing that h-IAPP oligomers activate the inflammasome (Johnson et al., 2012; Masters et al., 2010; Park et al., 2012), and recent findings that extracellular h-IAPP oligomers can be transported into b-cells (Trikha and…”
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“Comparably, hIAPP can form proinflammatory oligomers and fibrils that contribute to islet inflammation by recruiting and activating macrophages in vivo.(39,76) Nevertheless, the role of hIAPP and ER stress still needs to be elucidated.”
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“of type 2 diabetes [4, 5], atherosclerosis [6], Alzheimer’s disease”
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“demonstrated that amylin, known also as islet amyloid polypeptide (IAPP), which is secreted by pancreatic β cells besides insulin, can be converted from a soluble to amyloid form and can activate the NLRP3 inflammasome in mouse macrophages (Figure 2) [220].”
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“The precise mechanism by which IL-1β is overproduced in type 2 diabetes remains to be fully elucidated, but recent research has demonstrated an amylin-induced activation of the NLRP3 inflammasome as a mechanism [14,15].”
BackgroundRRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor
Chen, Y., He, H., Lin, B., Chen, Y., Deng, X., Jiang, W., & Zhou, R. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00683-y · Cited by 142
Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis
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“Given the role of IL-1b in diseases such as type 2 diabetes [8], gout [7] and osteoarthritis [37], which all involve NLRP3, a small molecule such as CRID3 could have promise therapeutically and be an alternative to IL-1b biologics such as the anti-IL-1b antibody Canakinumab and the IL-1 Trap Rilonacept.”
BackgroundSelf-citationDisease-associated amyloid and misfolded protein aggregates activate the inflammasome
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Self-citationMacrophages and islet inflammation in type 2 diabetes
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“The second stimulus was identified as islet amyloid polypeptide (IAPP), which is secreted from β-cells in response to high glucose and is a unique polypeptide constituent of amyloid found in pancreatic islets [36].”
BackgroundBiochemical regulation of the inflammasome
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“Endogenous activators include host derived molecules which are typically “crystalline” or polymeric in nature and associated with danger, damage or cell death (Masters & O’Neill, 2011) including cholesterol crystals (Rock et al., 2010), islet amyloid polypeptide (IAPP) (Masters et al., 2010), amyloid β, hyaluron, mono…”
BackgroundInfluentialSelf-citationThe β-cell assassin: IAPP cytotoxicity
Raleigh, D. P., Zhang, X., Hastoy, B., & Clark, A. (2017) · Journal of Molecular Endocrinology · doi:10.1530/jme-17-0105 · Cited by 138
“The molecular complex 617 known as the inflammasome has been implicated in release of cytokines in hIAPP induced 618 cell death (Masters et al. 2010).”
BackgroundInflammasomes: sensors of metabolic stresses for vascular inflammation
Yang, X.-F. (2013) · Frontiers in Bioscience · doi:10.2741/4127 · Cited by 134
“Recently studies have demonstrated that several endogenous metabolic stress molecules, such as oligomers of islet amyloid polypeptide (3), glucose (4), ceramid (5), oxidized low density lipoprotein(6) and cholesterol crystals, can be sensed by NLRP3 (nucleotide-binding domain and leucine-rich repeat containing (NLR) f…”
BackgroundInflammasomes and Metabolic Disease
Henao‐Mejia, J., Elinav, E., Thaiss, C. A., & Flavell, R. A. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170324 · Cited by 176
Inflammasome biology, molecular pathology and therapeutic implications
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“Among them, we will focus on Alzheimer, Type 2 diabetes (T2D), obesity, gout and atherosclerosis.”
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Intrinsic and Extrinsic Regulation of Innate Immune Receptors
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P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation
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“Masters et al (20) found that oxLDL upregulated IL-1β mRNA expression and promoted the release of IL-1β by mouse bone marrow-derived macrophages.”
BackgroundInfluentialIAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo
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Inflammasomes: Molecular Regulation and Implications for Metabolic and Cognitive Diseases
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“Recently, IAPP was also found to engage the NLRP3 inflammasome and produce IL-1b in bone marrow-derived macrophages (BMDMs) that were primed by products of heightened glucose metabolism (33).”
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“2 and 3), which has been shown to be involved in type 2 diabetes (30,31).”
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“(IAPP or amilin), a hallmark feature in the pancreas of most patients with T2D, triggeres IL-1β production via NLPR3 in lipopolysaccharide (LPS)-primed macrophages or dendritic cells (124).”
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“Moreover, IL-1β increases the deposition of amyloid, which contributes further to β-cell loss (77).”
BackgroundAnti-dsDNA antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/macrophages
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“Glyburide, which specifically inhibits NLPR3 inflammasome activation [10], was used to inhibit NLRP3, and capase-1 inhibitor YVAD was used to inhibit caspase-1.”
The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders
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The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation
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“Inhibition of IRE1α with 4µ8C or tauroursodeoxycholic acid (TUDCA) which alleviates ER stress, or silencing of Ern1, has no effect on LPS + ATP-induced caspase-1 maturation and IL-1β secretion in BMDMs [73].”
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“Recently, studies showed that IAPP aggregates may actively contribute to islet dysfunction in T2D by provoking an inflammatory response [31, 33].”
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“Among the stimuli that activate NLRP3 are fatty acids and the islet amyloid polypeptide (5, 6), which are associated with obesity and type 2 diabetes.”
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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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