Downregulated XBP-1 Rescues Cerebral Ischemia/Reperfusion Injury-Induced Pyroptosis via the NLRP3/Caspase-1/GSDMD Axis

Figure 5

A schematic diagram for the mechanisms of XBP-1 in the regulation of neuronal pyroptosis following cerebral ischemia. The expression of XBP-1 is upregulated after cerebral ischemia/reperfusion. Cerebral ischemia/reperfusion mediates Xbp-1u mRNA splicing to generate the active XBP-1s form. Active XBP-1s promotes NLRP3-ASC/Caspase-1 inflammasome assembly, which generates inflammatory mediators and cytokines. The triggered Caspase-1 cleaves GSDMD to promote the release of the N-terminal domain, which executes pore formation on the neuronal membrane. The mature forms of IL-1β and IL-18 that are secreted through these pores are also increased. Downregulated XBP-1 can facilitate an anti-inflammatory effect and inhibit pyroptosis. XBP-1: X-box binding protein l splicing; NLRP3: NOD-, LRR-, and pyrin domain-containing 3; ASC: speck-like protein containing a CARD; GSDMD: gasdermin D; GSDMD-N: N-terminal GSDMD domain; IL-1β: interleukin-1β; IL-18: interleukin-18.