Abstract
SummaryPyroptosis has emerged as a key mechanism by which inflammasomes promote host defense against microbial pathogens and sterile inflammation. Gasdermin D (GSDMD)-mediated cell lysis is a hallmark of pyroptosis, but our understanding of cell death signaling during pyroptosis is fragmented. Here, we show that independently of GSDMD-mediated plasma membrane permeabilization, inflammasome receptors engage caspase-1 and caspase-8, both of which redundantly promote activation of apoptotic executioner caspase-3 and caspase-7 in pyroptotic macrophages. Impaired GSDMD pore formation downstream of caspase-1 and caspase-8 activation suffices to unmask the apoptotic phenotype of pyroptotic macrophages. Combined inactivation of initiator caspase-1 and caspase-8, or executioner caspase-3 and caspase-7, is required to abolish inflammasome-induced DEVDase activity during pyroptosis and in apoptotic Gsdmd−/− cells. Collectively, these results unveil a robust apoptotic caspase network that is activated in parallel to GSDMD-mediated plasma membrane permeabilization and safeguards cell death induction in pyroptotic macrophages.
Highlights
Pyroptosis is initiated downstream of inflammasome assembly in activated innate immune cells (Broz and Dixit, 2016; Lamkanfi and Dixit, 2014)
We and others previously demonstrated that apoptosis-associated speck-like protein containing a CARD (ASC) specks serve as cytosolic scaffolds for inflammasome-mediated caspase-8 activation and induction of apoptosis in caspase-1-deficient macrophages in response to stimuli of the Nlrc4, Nlrp1b, AIM2, or Nlrp3 inflammasome pathways (Lee et al, 2018; Pierini et al, 2012; Puri et al, 2012; Sagulenko et al, 2013; Van Opdenbosch et al, 2017)
Impaired Gasdermin D (GSDMD) pore formation downstream of caspase-1 and caspase-8 activation sufficed to unmask the apoptotic phenotype of pyroptotic macrophages. These results unveil a robust apoptotic caspase network that is activated in parallel to GSDMD-mediated plasma membrane permeabilization to safeguard cell death induction in pyroptotic macrophages
Summary
Pyroptosis is initiated downstream of inflammasome assembly in activated innate immune cells (Broz and Dixit, 2016; Lamkanfi and Dixit, 2014). Pyroptosis induction by inflammasomes is considered a linear pathway in which murine inflammatory caspase-1 and caspase-11 and human caspase-1, caspase-4, and caspase-5 cleave gasdermin D (GSDMD) to release the N-terminal GSDMDN domain that forms higher-order oligomeric pores in the plasma membrane to induce osmotic swelling and early cell lysis (Aglietti et al, 2016; Ding et al, 2016; Kayagaki et al, 2015; Liu et al, 2016; Sborgi et al, 2016; Shi et al, 2015) This is in marked contrast to apoptosis, in which parallel maturation of apoptotic executioner caspase-3 and caspase-7 by initiator caspase-8 and caspase-9 results in cleavage of hundreds of substrates that orchestrates the coordinated disassembly of the cell without spilling the intracellular content in the extracellular environment (Nagata and Tanaka, 2017). The molecular mechanisms in inflammasome-activated macrophages that regulate the switch from pyroptosis to apoptosis signaling remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
