Fig. 2: Types of pyroptotic cell death after stroke.

After stroke, dormant microglia first rush to the damaged area and polarize into M1 and M2 types to exert pro-inflammatory and anti-inflammatory effects, respectively. However, under various stressful stimuli, microglia undergo pyroptosis and are converted to the M1 type, aggravating brain damage. Pro-inflammatory factors stimulate astrocytes to undergo pyroptosis, leading to increased membrane osmotic pressure and consequent water absorption and swelling, ultimately causing massive brain edema after stroke. Neuronal cells are more likely to undergo pyroptosis after losing the protection of astrocytes, resulting in irreversible brain damage. Pro-inflammatory substances released by microglia and astrocytes, among others, contribute to the pyroptosis of BMECs, accelerating the disruption of the BBB. In addition, GSDMD may exert other unknown effects in neutrophils; it seems to promote the release of NETs to induce secondary phagocytosis rather than directly triggering neutrophil rupture and death. IL-10 interleukin-10, TGF-β transforming growth factor-β, IL-18 interleukin-18, IL-1β interleukin-1β, GSDMD gasdermin D, dsDNA double-stranded DNA, TNF-α tumor necrosis factor-α, iNOS induced nitrogen monoxide synthase, PN-OP protein nanoparticle-induced osmotic pressure, AIM2 absent in melanoma 2, TLR4 toll-like receptor 4, CCR5 CC-chemokine receptor 5, CXCR4 chemokine (C-X-C motif) receptor 4, NLRP1 NOD-like receptor thermal protein domain associated protein 1, NLRP3 NOD-like receptor thermal protein domain associated protein 3, BBB blood-brain barrier, MMP-9 matrix metalloproteinase-9, BMECs brain microvascular endothelial cells, ELANE neutrophil elastase, NETs neutrophil extracellular traps.