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

• Published in: Molecular and cellular endocrinology 2018-12, Vol.478, p.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: Article
• Language: English
• Subjects: ASC; Danger associated-molecular patterns; Inflammation; Potassium; Purinergic receptors
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2018.08.001

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.