FIGURE 5.

Inhibition of caspase-8 following TNF-receptor or TLR2/4 ligation results in execution of RIPK1-dependent necroptosis in microglia. Activation of TNF-receptor by TNF is known to induce formation of a large receptor-bound “complex I” that mediates activation of NF-κB. Complex I formation can be followed by formation in the cytosol of “complex II,” where caspase-8 in complex with cFLIP-L suppresses RIPK1 necroptotic activity. Inhibition of caspase-8 results in deinhibition of RIPK1 and formation of the necroptosis induction of necroptosis with RIPK3. TLR ligation also results in prosurvival caspase-8 activity, potentially by recruitment via the adaptor molecule TRIF of complex II or “ripoptosome”-like protein complexes. The RIPK-1 inhibitor necrostatin-1 prevents induction of necroptosis through inhibition of RIPK-1 kinase activity.