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An Apoptotic Caspase Network Safeguards Cell Death Induction in Pyroptotic Macrophages

de Vasconcelos, N;Van Opdenbosch, N;Van Gorp, H;Martn-Prez, R;Zecchin, A;Vandenabeele, P;Lamkanfi, M;

Pyroptosis has emerged as a powerful defense mechanism of the host against microbial pathogens. It also drives detrimental autoinflammation, sepsis and NASH by promoting passive secretion of IL-1 and alarmins. Inflammatory caspase-mediated GSDMD maturation and GSDMD pore-driven cell lysis are hallmark events of pyroptosis, but our understanding of the biochemical events that underpin pyroptosis is incomplete. Here, we show that an apoptotic caspase network is activated parallelly to GSDMD-mediated plasma membrane permeabilization in pyroptotic macrophages. Caspases 1 and 8 in pyroptotic cells both activate apoptotic executioner caspases 3 and 7, and combined inactivation of caspases 3 and 7 is required to abolish DEVDase activity and cleavage of hallmark apoptotic caspase substrates. Akin to Gsdmd-deficient cells, macrophages from homozygous GsdmdI105N mutant mice display an apoptotic morphology, indicating that defective GSDMD pore formation downstream of caspase-1-mediated GSDMD cleavage and plasma membrane translocation suffices to unmask the apoptotic phenotype of pyroptotic cells. Moreover, combined loss of caspases 3 and 7 was required to abolish Nlrp1b, Nlrc4 and Nlrp3 inflammasome-induced DEVDase activity and cell death induction in Gsdmd-deficient macrophages. Collectively, these results unveil an apoptotic caspase signaling network that is activated in pyroptotic cells parallelly to GSDMD-mediated cell lysis, and provide mechanistic insight into how inactivation of caspase-1 and GSDMD promotes inflammasome-induced apoptosis through distinct signaling pathways.