The data here demonstrate that TXNIP is a critical signaling node that links ER stress and IL-1β production. TXNIP expression is induced by ER stress under the IRE1α and PERK-eIF2α pathways of the UPR. Transcriptionally TXNIP expression is regulated by ChREBP and ATF5. An accompanying manuscript from Drs. Feroz Papa and Scott Oakes revealed that IRE1α regulates TXNIP expression at the post-transcriptional level, which may be complementary to PERK's transcriptional control. As a result TXNIP induces IL-1β production through the activation of NLRP3 inflammasome and IL-1β mRNA transcription, leading to β cell death.
Recent experimental, clinical, and genetic evidence suggests that ER stress-mediated β cell dysfunction and death contribute to the pathogenesis of type 1 and type 2 diabetes as well as genetic forms of diabetes such as Wolfram syndrome and permanent neonatal diabetes (Eizirik et al., 2008
; Kaufman, 2011
; Oslowski and Urano, 2011
; Tersey et al., 2012
). However, the mechanisms involved and pathological contributions remain elusive. Here we propose that during diabetes, TXNIP expression is induced through the UPR and leads to β cell inflammation and apoptosis.
Inflammation is a critical component leading to β cell dysfunction and death in type and type 2 diabetes. (Atkinson et al., 2011
; Bluestone et al., 2010
; Corbett et al., 1993
; Eizirik et al., 2009
; Larsen et al., 2007
). There has been substantial interest in identifying pathways initiating inflammation. A variety of inflammatory pathways have been associated with IL-1β production. However, essential factors initiating inflammation by IL-1β production in β cells have been elusive. Our findings unexpectedly revealed that the UPR regulates IL-1β production through TXNIP. ER stress-mediated upregulation of TXNIP leads to IL-1β secretion through inflammasome activation. Secreted IL-1β is capable of binding to IL-1 receptor on β cell surface, which may lead to induction of its own expression. It is also possible that TXNIP upregulation by ER stress may be involved in the transcriptional activation of IL-1β (Koenen et al., 2011
). Our findings suggest that environmental and genetic factors that can elicit ER stress are promising candidates for crucial factors initiating inflammation in β cells.
It has been shown that TXNIP expression is increased by high glucose in human islets and plays an important role in glucose toxicity (Hui et al., 2008
; Oka et al., 2009
; Shalev et al., 2002
; Yoshihara et al., 2010
). We have previously shown that chronic high glucose leads to unresolvable ER stress in β cells, leading to β cell dysfunction and death (Lipson et al., 2006
; Lipson et al., 2008
). Thus, TXNIP upregulation by high glucose could be mediated by the UPR. TXNIP has been also shown to be a critical signaling molecule linking oxidative stress to inflammasome activation (Zhou et al., 2010
). These findings, combined with our data, indicate that a variety of stress signaling pathways converge at TXNIP, leading to inflammasome activation and IL-1β production.
ER stress and inflammation are critical pathogenic components of β cell dysfunction and death in diabetes. Our data combined with recent findings indicate that there exists a tight link between ER stress, oxidative stress, glucose toxicity, and inflammation, suggesting that a therapeutic strategy that aims to target the common molecular processes that are altered in stressed β cells might be effective. TXNIP provides such a target.