Finally, we reasoned that because IRE1α controls TXNIP induction, we may be able to reduce TXNIP and IL-1β by inhibiting IRE1α with small molecules. Recently, a cell-permeable small molecule—called STF-083010—capable of covalently inhibiting IRE1α RNase was described (Papandreou et al., 2011). We re-synthesized STF-083010 and tested its ability to prevent IRE1α activation. Figure 6F shows complete inhibition of IRE1α-mediated XBP1 mRNA splicing by STF-083010 when provided to cells before exposure to Tm. Note that treatment with ATP does not trigger ER stress, as evidenced by unchanged XBP1 mRNA splicing, but interestingly, STF-083010 can reduce basal levels of XBP1 mRNA splicing even in the ATP-treated cells. Strikingly, STF-083010 pre-treatment prevents production of TXNIP under forcible IRE1α activation (Figure 6G). Furthermore, provision of STF-083010 effectively shuts off secretion of IL-1β during treatment with Tg, but not ATP (Figure 6H).. This indicates that ER stress signals to the NLRP3 inflammasome can be specifically blocked by a small molecule targeting the proximal UPR sensor, IRE1α, while still allowing other DAMP signals to be relayed.
