words) 28Inflammasome-induced pyroptosis comprises a key cell-autonomous immune process 29 against intracellular bacteria, namely the generation of dying cell structures. These so-30 called pore-induced intracellular traps (PITs) entrap and weaken intracellular microbes. 31However, the immune importance of pyroptosis against extracellular pathogens remains 32 unclear. Here, we report that Type-3 secretion system (T3SS)-expressing Pseudomonas 33 aeruginosa (P. aeruginosa) escaped PIT immunity by inducing a NLRC4 inflammasome-34 dependent macrophage pyroptosis response in the extracellular environment. To the 35 contrary, phagocytosis of Salmonella Typhimurium promoted NLRC4-dependent PIT 36 formation and the subsequent bacterial caging. Remarkably, T3SS-deficient 37Pseudomonas were efficiently sequestered within PIT-dependent caging, which favored 38 exposure to neutrophils. Conversely, both NLRC4 and caspase-11 deficient mice 39 presented increased susceptibility to T3SS-deficient P. aeruginosa challenge, but not to 40 T3SS-expressing P. aeruginosa. Overall, our results uncovered that P. aeruginosa uses its 41 T3SS to overcome inflammasome-triggered pyroptosis, which is primarily effective against 42 intracellular invaders. 43 44 45 46 47 48 Importance (119 words) 55Although innate immune components confer host protection against infections, the 56 opportunistic bacterial pathogen Pseudomonas aeruginosa (P. aeruginosa) exploits the 57 inflammatory reaction to thrive. Specifically the NLRC4 inflammasome, a crucial immune 58 complex, triggers an Interleukin (IL)-1β and -18 deleterious host response to P. 59 aeruginosa. Here, we provide evidence that, in addition to IL-1 cytokines, P. aeruginosa 60 also exploits the NLRC4 inflammasome-induced pro-inflammatory cell death, namely 61 pyroptosis, to avoid efficient uptake and killing by macrophages. Therefore, our study 62 reveals that pyroptosis-driven immune effectiveness mainly depends on P. aeruginosa 63 localization. This paves the way toward our comprehension of the mechanistic 64 requirements for pyroptosis effectiveness upon microbial infections and may initiate 65 targeted approaches in order to ameliorate the innate immune functions to infections. 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 4 Manuscript length (5621 words) 82Activation of the NLRC4 inflammasome follows an original path as it requires 93 additional helper NLRsthe neuronal apoptosis inhibitory proteins (NAIPs)that, upon 94 ligand recognition, form hetero-oligomeric complexes with NLRC4 and promote its 95 activation (4-10). Both NAIP5 and NAIP6 directly recognize cytosolic flagellin while NAIP-96 1 and -2 detect the type-3 secretion system (T3SS) apparatus needle and rod subunits, 97 respectively (1, 6). Importantly, resulting IL-1β and IL-18 cytokine secretion mediates 98 intracellular bacterial clearance by inducing, respectively, phagocyte recruitment and the 99