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Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates.

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Title: Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates.
Authors: Westwell-Roper, Clara1, Denroche, Heather C.2, Ehses, Jan A.2, Verchere, C. Bruce1,2 bverchere@cfri.ca
Source: Journal of Biological Chemistry. 4/22/2016, Vol. 291 Issue 17, p8908-8917. 10p.
Subjects: Amyloid beta-protein, Pancreatic beta cells, Natural immunity, Islands of Langerhans, Polypeptides, Type 2 diabetes
Abstract: Aggregation of islet amyloid polypeptide (IAPP) contributes to beta cell dysfunction in type 2 diabetes and islet transplantation. Like other amyloidogenic peptides, human IAPP induces macrophage IL-1β secretion by stimulating both the synthesis and processing of proIL-1β, a pro-inflammatory cytokine that (when chronically elevated) impairs beta cell insulin secretion. We sought to determine the specific mechanism of IAPP-induced proIL-1β synthesis. Soluble IAPP species produced early during IAPP aggregation provided a Toll-like-receptor-2- (TLR2-) dependent stimulus for NF-κB activation in HEK 293 cells and bone marrow-derived macrophages (BMDMs). Nonamyloidogenic rodent IAPP and thioflavin-T-positive fibrillar amyloid produced by human IAPP aggregation failed to activate TLR2. Blockade of TLR6 but not TLR1 prevented hIAPP-induced TLR2 activation, consistent with stimulation of a TLR2/6 heterodimer. TLR2 and its downstream adaptor protein MyD88 were required for IAPP-induced cytokine production by BMDMs, a process that is partially dependent on autoinduction by IL-1.BMDMstreated with soluble but not fibrillar IAPP provided a TLR2-dependent priming stimulus for ATP-induced IL-1β secretion, whereas late IAPP aggregates induced NLRP3- dependent IL-1β secretion by LPS-primed macrophages. Moreover, inhibition of TLR2 and depletion of islet macrophages prevented up-regulation of Il1b and Tnf expression in human IAPP-expressing transgenic mouse islets. These data suggest participation by both soluble and fibrillar aggregates in IAPPinduced islet inflammation. IAPP-induced activation of TLR2 and secretion of IL-1 may be important therapeutic targets to prevent amyloid-associated beta cell dysfunction. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates.
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  Data: <searchLink fieldCode="AR" term="%22Westwell-Roper%2C+Clara%22">Westwell-Roper, Clara</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Denroche%2C+Heather+C%2E%22">Denroche, Heather C.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Ehses%2C+Jan+A%2E%22">Ehses, Jan A.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Verchere%2C+C%2E+Bruce%22">Verchere, C. Bruce</searchLink><relatesTo>1,2</relatesTo><i> bverchere@cfri.ca</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 4/22/2016, Vol. 291 Issue 17, p8908-8917. 10p.
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  Data: <searchLink fieldCode="DE" term="%22Amyloid+beta-protein%22">Amyloid beta-protein</searchLink><br /><searchLink fieldCode="DE" term="%22Pancreatic+beta+cells%22">Pancreatic beta cells</searchLink><br /><searchLink fieldCode="DE" term="%22Natural+immunity%22">Natural immunity</searchLink><br /><searchLink fieldCode="DE" term="%22Islands+of+Langerhans%22">Islands of Langerhans</searchLink><br /><searchLink fieldCode="DE" term="%22Polypeptides%22">Polypeptides</searchLink><br /><searchLink fieldCode="DE" term="%22Type+2+diabetes%22">Type 2 diabetes</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Aggregation of islet amyloid polypeptide (IAPP) contributes to beta cell dysfunction in type 2 diabetes and islet transplantation. Like other amyloidogenic peptides, human IAPP induces macrophage IL-1β secretion by stimulating both the synthesis and processing of proIL-1β, a pro-inflammatory cytokine that (when chronically elevated) impairs beta cell insulin secretion. We sought to determine the specific mechanism of IAPP-induced proIL-1β synthesis. Soluble IAPP species produced early during IAPP aggregation provided a Toll-like-receptor-2- (TLR2-) dependent stimulus for NF-κB activation in HEK 293 cells and bone marrow-derived macrophages (BMDMs). Nonamyloidogenic rodent IAPP and thioflavin-T-positive fibrillar amyloid produced by human IAPP aggregation failed to activate TLR2. Blockade of TLR6 but not TLR1 prevented hIAPP-induced TLR2 activation, consistent with stimulation of a TLR2/6 heterodimer. TLR2 and its downstream adaptor protein MyD88 were required for IAPP-induced cytokine production by BMDMs, a process that is partially dependent on autoinduction by IL-1.BMDMstreated with soluble but not fibrillar IAPP provided a TLR2-dependent priming stimulus for ATP-induced IL-1β secretion, whereas late IAPP aggregates induced NLRP3- dependent IL-1β secretion by LPS-primed macrophages. Moreover, inhibition of TLR2 and depletion of islet macrophages prevented up-regulation of Il1b and Tnf expression in human IAPP-expressing transgenic mouse islets. These data suggest participation by both soluble and fibrillar aggregates in IAPPinduced islet inflammation. IAPP-induced activation of TLR2 and secretion of IL-1 may be important therapeutic targets to prevent amyloid-associated beta cell dysfunction. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1074/jbc.M115.712455
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        Text: English
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        Type: general
      – SubjectFull: Pancreatic beta cells
        Type: general
      – SubjectFull: Natural immunity
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      – SubjectFull: Islands of Langerhans
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      – SubjectFull: Polypeptides
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      – SubjectFull: Type 2 diabetes
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      – TitleFull: Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates.
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            NameFull: Denroche, Heather C.
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            NameFull: Ehses, Jan A.
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              Text: 4/22/2016
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