Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis

Seyed Mojtaba Ghiasi; Mattias Salling Dahllöf; Yama Osmai; Mirwais Osmai; Kathrine Kronberg Jakobsen; Alexander Aivazidis; Björn Tyrberg; Lisa Perruzza; Michala Cecilie Burstein Prause; Dan Ploug Christensen; Morten Fog-Tonnesen; Morten Lundh; Fabio Grassi; Lucienne Chatenoud; Thomas Mandrup-Poulsen

doi:10.1016/j.mce.2018.08.001

Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis

Seyed Mojtaba Ghiasi, Mattias Salling Dahllöf, Yama Osmai, Mirwais Osmai, Kathrine Kronberg Jakobsen, Alexander Aivazidis, Björn Tyrberg, Lisa Perruzza, Michala Cecilie Burstein Prause, Dan Ploug Christensen, Morten Fog-Tonnesen, Morten Lundh, Fabio Grassi, Lucienne Chatenoud, Thomas Mandrup-Poulsen

8 Citationer (Scopus)

Abstract

β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1β+IFNγ in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K+ reduced cytokine-induced apoptosis and NO production and restored cytokine-inhibited accumulated insulin-secretion. Basal inflammasome expression was JNK1-3 dependent. Knock-down of the ASC interaction domain common for NLRP1 and 3 improved insulin secretion and ameliorated IL-1β and/or glucolipotoxicity-induced cell death and reduced cytokine-induced NO-production. Broad inflammasome-inhibition, but not NLRP3-selective inhibition, protected against IL-1β-induced INS-1 cell-toxicity. We suggest that IL-1β causes β-cell toxicity in part by NLRP1 mediated caspase-1-activation and maturation of IL-1β leading to an autocrine potentiation loop.

Originalsprog	Engelsk
Tidsskrift	Molecular and Cellular Endocrinology
Vol/bind	478
Sider (fra-til)	106-114
ISSN	0303-7207
DOI	https://doi.org/10.1016/j.mce.2018.08.001
Status	Udgivet - 2018

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10.1016/j.mce.2018.08.001

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Ghiasi, S. M., Dahllöf, M. S., Osmai, Y., Osmai, M., Jakobsen, K. K., Aivazidis, A., Tyrberg, B., Perruzza, L., Prause, M. C. B., Christensen, D. P., Fog-Tonnesen, M., Lundh, M., Grassi, F., Chatenoud, L., & Mandrup-Poulsen, T. (2018). Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis. Molecular and Cellular Endocrinology, 478, 106-114. https://doi.org/10.1016/j.mce.2018.08.001

Ghiasi, SM, Dahllöf, MS, Osmai, Y, Osmai, M, Jakobsen, KK, Aivazidis, A, Tyrberg, B, Perruzza, L, Prause, MCB, Christensen, DP, Fog-Tonnesen, M, Lundh, M, Grassi, F, Chatenoud, L & Mandrup-Poulsen, T 2018, 'Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis', Molecular and Cellular Endocrinology, bind 478, s. 106-114. https://doi.org/10.1016/j.mce.2018.08.001

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abstract = "β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1β+IFNγ in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K+ reduced cytokine-induced apoptosis and NO production and restored cytokine-inhibited accumulated insulin-secretion. Basal inflammasome expression was JNK1-3 dependent. Knock-down of the ASC interaction domain common for NLRP1 and 3 improved insulin secretion and ameliorated IL-1β and/or glucolipotoxicity-induced cell death and reduced cytokine-induced NO-production. Broad inflammasome-inhibition, but not NLRP3-selective inhibition, protected against IL-1β-induced INS-1 cell-toxicity. We suggest that IL-1β causes β-cell toxicity in part by NLRP1 mediated caspase-1-activation and maturation of IL-1β leading to an autocrine potentiation loop.",

author = "Ghiasi, {Seyed Mojtaba} and Dahll{\"o}f, {Mattias Salling} and Yama Osmai and Mirwais Osmai and Jakobsen, {Kathrine Kronberg} and Alexander Aivazidis and Bj{\"o}rn Tyrberg and Lisa Perruzza and Prause, {Michala Cecilie Burstein} and Christensen, {Dan Ploug} and Morten Fog-Tonnesen and Morten Lundh and Fabio Grassi and Lucienne Chatenoud and Thomas Mandrup-Poulsen",

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year = "2018",

doi = "10.1016/j.mce.2018.08.001",

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volume = "478",

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T1 - Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis

AU - Ghiasi, Seyed Mojtaba

AU - Dahllöf, Mattias Salling

AU - Osmai, Yama

AU - Osmai, Mirwais

AU - Jakobsen, Kathrine Kronberg

AU - Aivazidis, Alexander

AU - Tyrberg, Björn

AU - Perruzza, Lisa

AU - Prause, Michala Cecilie Burstein

AU - Christensen, Dan Ploug

AU - Fog-Tonnesen, Morten

AU - Lundh, Morten

AU - Grassi, Fabio

AU - Chatenoud, Lucienne

AU - Mandrup-Poulsen, Thomas

PY - 2018

Y1 - 2018

N2 - β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1β+IFNγ in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K+ reduced cytokine-induced apoptosis and NO production and restored cytokine-inhibited accumulated insulin-secretion. Basal inflammasome expression was JNK1-3 dependent. Knock-down of the ASC interaction domain common for NLRP1 and 3 improved insulin secretion and ameliorated IL-1β and/or glucolipotoxicity-induced cell death and reduced cytokine-induced NO-production. Broad inflammasome-inhibition, but not NLRP3-selective inhibition, protected against IL-1β-induced INS-1 cell-toxicity. We suggest that IL-1β causes β-cell toxicity in part by NLRP1 mediated caspase-1-activation and maturation of IL-1β leading to an autocrine potentiation loop.

AB - β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1β+IFNγ in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K+ reduced cytokine-induced apoptosis and NO production and restored cytokine-inhibited accumulated insulin-secretion. Basal inflammasome expression was JNK1-3 dependent. Knock-down of the ASC interaction domain common for NLRP1 and 3 improved insulin secretion and ameliorated IL-1β and/or glucolipotoxicity-induced cell death and reduced cytokine-induced NO-production. Broad inflammasome-inhibition, but not NLRP3-selective inhibition, protected against IL-1β-induced INS-1 cell-toxicity. We suggest that IL-1β causes β-cell toxicity in part by NLRP1 mediated caspase-1-activation and maturation of IL-1β leading to an autocrine potentiation loop.

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U2 - 10.1016/j.mce.2018.08.001

DO - 10.1016/j.mce.2018.08.001

M3 - Journal article

C2 - 30121202

SN - 0303-7207

VL - 478

SP - 106

EP - 114

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

ER -

Regulation of the beta-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis

Abstract

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