Biological Effects and Mechanisms of Caspases in Early Brain Injury after Subarachnoid Hemorrhage

Figure 3

Pyroptosis pathway in SAH. Pyroptosis is an inflammatory form of cell death that is stimulated in SAH by intracellular sensor proteins such as NLRP3 (used as an example here) or AIM2 that detect damage-associated molecular patterns (DAMPs) or cytoplasmic double-stranded DNA (dsDNA). Upon receiving these stimuli, these sensors recruit an adaptor, the apoptosis-related speck-like protein ASC, which in turn recruit procaspase-1 to form the inflammasome complex and activate caspase-1 within it. The activation of caspase-1 cleaves precursors of the interleukin-1 family cytokines IL-1β and IL-18. In addition, caspase-1 also activates gasdermin D (GSDMD), causing its N-terminal domain to be cleaved and forming a pore (GSDMD pore) in the plasma membrane. Mature IL-1β and IL18 are released along the GSDMD pore and cause cell swelling eventually triggering pyroptosis. Moreover, both the broad-spectrum caspase inhibitor Z-VAD-FMK and caspase-1-specific inhibitors (VX-765 and Ac-YVAD-CMK) can alleviate EBI after SAH by inhibiting the caspase-1-mediated pyroptosis pathway.