Amyloid formation disrupts the balance between interleukin-1β and interleukin-1 receptor antagonist in human islets

Abstract

Objectivesβ-cell dysfunction and apoptosis associated with islet inflammation play a key role in the pathogenesis of type 2 diabetes (T2D). Growing evidence suggests that islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to islet inflammation and β-cell death in T2D. We recently showed the role of interleukin-1β (IL-1β)/Fas/caspase-8 apoptotic pathway in amyloid-induced β-cell death. In this study, we used human islets in culture as an ex vivo model of amyloid formation to: (1) investigate the effects of amyloid on islet levels of the natural IL-1 receptor antagonist (IL-1Ra); (2) examine if modulating the IL-1β/IL-1Ra balance can prevent amyloid-induced β-cell Fas upregulation and apoptosis.MethodsIsolated human islets (n = 10 donors) were cultured in elevated glucose (to form amyloid) with or without a neutralizing human IL-1β antibody for up to 7 days. Parallel studies were performed with human islets in which amyloid formation was prevented by adeno-siRNA-mediated suppression of hIAPP expression (as control). β-cell levels of IL-1Ra, Fas, apoptosis as well as islet function, insulin- and amyloid-positive areas, and IL-1Ra release were assessed.ResultsProgressive amyloid formation in human islets during culture was associated with alterations in IL-1Ra. Islet IL-1Ra levels were higher at early stages but were markedly reduced at later stages of amyloid formation. Furthermore, IL-1Ra release from human islets was reduced during 7-day culture in a time-dependent manner. These changes in IL-1Ra production and release from human islets during amyloid formation adversely correlated with islet IL-1β levels, β-cell Fas expression and apoptosis. Treatment with IL-1β neutralizing antibody markedly reduced amyloid-induced β-cell Fas expression and apoptosis, thereby improving islet β-cell survival and function during culture.ConclusionsThese data suggest that amyloid formation impairs the balance between IL-1β and IL-1Ra in islets by increasing IL-1β production and reducing IL-1Ra levels thereby promoting β-cell dysfunction and death. Restoring the IL-1β/IL-1Ra ratio may provide an effective strategy to protect islet β-cells from amyloid toxicity in T2D.

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

“…Moreover, hIAPP transgenic mice fed a high-fat diet for 12 months have dramatically elevated proinflammatory gene expression in islets including Ccl2, Cxcl1, Nlrp3, Pycard, Casp1, Il1b, Tnf, Il6, Adgre1 and Itgax (Meier et al 2014), the expression of which is strikingly higher than the effect of high-fat diet alone, supporting the idea that IAPP aggregates are a majorand perhaps essential -trigger for islet inflammation. Consistent findings have recently been reported in cultured human islets, demonstrating that islet amyloid formation correlates with increased IL1B and decreased levels of endogenous IL1 receptor antagonist, IL1RN (Hui et al 2017). Furthermore, inhibition of hIAPP expression or aggregation in human islets reduced IL1B levels .…”

“…Moreover, LPS-primed cells subsequently treated with hIAPP secrete approximately 10-fold greater levels of IL1B than cells treated with hIAPP only (Westwell-Roper et al 2016); this may explain why others have not observed robust IL1B secretion from cells stimulated with hIAPP alone compared to LPS-primed cells treated with hIAPP (Masters et al 2010, Sheedy et al 2013. The relative contributions of hIAPP-induced NFKB1 and NLRP3 activation in islet inflammation and ensuing beta cell dysfunction in vivo remain to be tested, though IL1 clearly plays a critical role, as IL1 antagonism ameliorates inflammation, and beta cell dysfunction and death, in hIAPP transgenic mice and isolated human islets (Westwell-Roper et al 2011, Hui et al 2017, Jin et al 2017. Furthermore, though occurring through distinct mechanisms, both priming and NLPR3 activation by IAPP are likely to perpetuate a feed-forward inflammatory activation in macrophages; we found that IL1 signalling potentiates further IAPP-induced IL1B secretion (Westwell-Roper et al 2011), and IL1B has also been shown to enhance islet amyloid formation in both human and hIAPP transgenic islets .…”

Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation

“…In islet cells, the expression of proinflammatory cytokines can be induced by the destruction of IAPP [41], hyperglycaemia [11,42] and free fatty acid stimulation [43]. The proinflammatory cytokines can cause b cell dysfunction [44] as well as dedifferentiation [45].…”

Inhibition of NLRP3 inflammasome by MCC950 improves the metabolic outcome of islet transplantation by suppressing IL-1β and islet cellular death

“…signalling through Toll-like receptors, caspase-1 is activated and cleaves pro-IL-1β to IL-1β [9][10][11] . Recent studies reported that NLRP3 inflammasome contributed to β cell dysfunction and death in type 1 and 2 diabetes 7,[12][13][14] . Furthermore, it affected the therapeutic effect of allogeneic organ transplantation 10 and worsened bacterial/viral infections 11 .…”