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

• Published in: Molecular and cellular endocrinology Vol. 478; pp. 106 - 114
• Main Authors: Ghiasi, Seyed Mojtaba, Dahllöf, Mattias Salling, Osmai, Yama, Osmai, Mirwais, Jakobsen, Kathrine Kronberg, Aivazidis, Alexander, Tyrberg, Björn, Perruzza, Lisa, Prause, Michala Cecilie Burstein, Christensen, Dan Ploug, Fog-Tonnesen, Morten, Lundh, Morten, Grassi, Fabio, Chatenoud, Lucienne, Mandrup-Poulsen, Thomas
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15.12.2018
• Subjects: Animals; apoptosis; Apoptosis - drug effects; ASC; autocrine signaling; CARD Signaling Adaptor Proteins; Cell Death - drug effects; Cell Line; Cytokines - pharmacology; Cytoprotection - drug effects; cytotoxicity; Danger associated-molecular patterns; Female; Glucose - toxicity; Histone Deacetylases - metabolism; Humans; inflammasomes; Inflammasomes - metabolism; Inflammation; insulin secretion; Insulin Secretion - drug effects; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; interleukin-1beta; Interleukin-1beta - metabolism; islets of Langerhans; JNK Mitogen-Activated Protein Kinases - metabolism; Lipids - toxicity; Middle Aged; nitric oxide; Potassium; Potassium - pharmacology; Purinergic receptors; Rats; Receptors, Purinergic P2X7 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stress, Physiological - drug effects; Young Adult; NO; Purinergic receptors; JNK; Inflammation; Danger associated-molecular patterns; NLRC; HDACi/KDACi; CARD; P2RX7; ASC; GSIS; KDAC; NLRP; KD; SFN; Potassium; HDAC
• DOI: 10.1016/j.mce.2018.08.001
• ISSN: 0303-7207; 1872-8057

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. [Display omitted] •β-cell NLRP1 is upregulated by cytokines via lysine deacetylases.•JNK2/3 knockdown increases basal β-cell NLRP3 expression.•JNK1-3 knockdown reduces basal β-cell cell ASC expression.•ASC deficiency improved insulin secretion and β-cell viability.•Broad, but not NLRP3 selective inflammasome inhibition reduced β-cell death.