Figure 6

Hypothesized model for molecular mechanism involved in necroptosis in brain tissues after ICH. After ICH occurs, microglia were rapidly activated and released an amount of inflammatory cytokines such as TNF-α. TNFR1 can spontaneously trimerize at the plasma membrane. When TNF-α binds to TNFR1, the conformation of these receptor trimers would be changed, allowing their cytosolic tails recruit multiple proteins, and then develop a complex (complex I) including TRADD (TNF-α receptor-associated death domain), RIP1, TRAF2 (TNFR associated factor 2), cIAP1 and cIAP2 (cellular inhibitor of apoptosis 1/2). Deubiquitylation of RIP1 mediates its transition from complex I to complex II, and then cooperates with RIP3 for recruitment of MLKL (mixed lineage kinase domain-like protein), FADD (FAS-associated protein with a death domain) and caspase-8. In this complex IIb, RIP1 and RIP3 are inhibited by caspase-8. When caspase-8 is inactive, complex IIb would carry out the TNF-α-mediated necroptotic pathway. Further, complex of MLKL and RIP3 transfers to the cell membrane and forms a channel, and then the internal flow of Ca²⁺ or Na⁺ is caused. Finally, the cell is dead by the necroptotic pathway. As necroptosis can further promote inflammation, it suggests that it can possibly have a positive feedback relationship between necroptosis and inflammation in brain injury after ICH.