Model of neutrophil responses to hyperactive T3SS ExoS⁺ or ExoS ADPRT^- P. aeruginosa.

(A) Hyperactive T3SS ExoS⁺ P. aeruginosa translocates flagellin and active ExoS into neutrophil. ExoS inhibits phagocytic signaling by targeting host proteins such as Ras. ExoS inhibits assembly of NLRC4 inflammasome in response to flagellin detection by NAIP. ExoS promotes formation of unknown pores in plasma membrane, allowing influx of Ca²⁺. Ca²⁺ enters the nucleus to activate Pad4, resulting in Cit3 generation, chromatin decondensation into cytosol, and incomplete NET extrusion due to maintenance of the cortical actin cytoskeleton. Pore formation triggers NINJ1 activation, PMR and release of LDH and HMGB1. Glycine inhibits activation of NINJ1 to prevent PMR. (B) Hyperactive T3SS ExoS ADPRT^- P. aeruginosa translocates flagellin and inactive ExoS into neutrophil. ExoS ADPRT^- fails to inhibit phagocytic signaling and assembly of NLRC4 inflammasome. ExoS ADPRT^- fails to promote pore formation and unleashes caspase-1 to cleave pro-IL-1β and GSDMD. N-GSDMD forms plasma membrane pores, allowing Ca²⁺ to enter the nucleus to activate Pad4, resulting in Cit3 generation, chromatin decondensation into cytosol, and incomplete NET extrusion. GSDMD pore formation triggers NINJ1 activation, PMR and release of LDH and HMGB1. Glycine inhibits activation of NINJ1 to prevent PMR.

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