Type-3 Secretion System–induced pyroptosis protects Pseudomonas against cell-autonomous immunity

Inflammasome-induced pyroptosis comprises a key cell-autonomous immune process against intracellular bacteria, namely the generation of dying cell structures. These so-called pore-induced intracellular traps (PITs) entrap and weaken intracellular microbes. However, the immune importance of pyroptosis against extracellular pathogens remains unclear. Here, we report that Type-3 secretion system (T3SS)-expressingPseudomonas aeruginosa(P. aeruginosa) escaped PIT immunity by inducing a NLRC4 inflammasome-dependent macrophage pyroptosis response in the extracellular environment. To the contrary, phagocytosis ofSalmonellaTyphimurium promoted NLRC4-dependent PIT formation and the subsequent bacterial caging. Remarkably, T3SS-deficientPseudomonaswere efficiently sequestered within PIT-dependent caging, which favored exposure to neutrophils. Conversely, both NLRC4 and caspase-11 deficient mice presented increased susceptibility to T3SS-deficientP. aeruginosachallenge, but not to T3SS-expressingP. aeruginosa.Overall, our results uncovered thatP. aeruginosauses its T3SS to overcome inflammasome-triggered pyroptosis, which is primarily effective against intracellular invaders.ImportanceAlthough innate immune components confer host protection against infections, the opportunistic bacterial pathogenPseudomonas aeruginosa(P. aeruginosa) exploits the inflammatory reaction to thrive. Specifically the NLRC4 inflammasome, a crucial immune complex, triggers an Interleukin (IL)-1β and -18 deleterious host response toP. aeruginosa. Here, we provide evidence that, in addition to IL-1 cytokines,P. aeruginosaalso exploits the NLRC4 inflammasome-induced pro-inflammatory cell death, namely pyroptosis, to avoid efficient uptake and killing by macrophages. Therefore, our study reveals that pyroptosis-driven immune effectiveness mainly depends onP. aeruginosalocalization. This paves the way toward our comprehension of the mechanistic requirements for pyroptosis effectiveness upon microbial infections and may initiate targeted approaches in order to ameliorate the innate immune functions to infections.Graphical abstractMacrophages infected with T3SS-expressingP. aeruginosadie in a NLRC4-dependent manner, which allows bacterial escape from PIT-mediated cell-autonomous immunity and neutrophil efferocytosis. However, T3SS-deficientP. aeruginosais detected by both NLRC4 and caspase-11 inflammasomes, which promotes bacterial trapping and subsequent efferocytosis ofP. aeruginosa-containing-PITs by neutrophils.