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Bacteria-released components can modulate host innate immune response in the absence of direct host cell–bacteria interaction. In particular, bacteria-derived outer membrane vesicles (OMVs) were recently shown to activate host caspase-11-mediated non-canonical inflammasome pathway  via  deliverance of OMV-bound lipopolysaccharide. However, further precise understanding of innate immune-modulation by bacterial OMVs remains elusive. Here, we present evidence that flagellated bacteria-released OMVs can trigger NLRC4 canonical inflammasome activation  via  flagellin delivery to the cytoplasm of host cells.  Salmonella typhimurium -derived OMVs caused a robust NLRC4-mediated caspase-1 activation and interleukin-1β secretion in macrophages in an endocytosis-dependent, but guanylate-binding protein-independent manner. Notably, OMV-associated flagellin is crucial for  Salmonella  OMV-induced inflammasome response. Flagellated  Pseudomonas aeruginosa -released OMVs consistently promoted robust NLRC4 inflammasome activation, while non-flagellated  Escherichia coli -released OMVs induced NLRC4-independent non-canonical inflammasome activation leading to NLRP3-mediated interleukin-1β secretion. Flagellin-deficient  Salmonella  OMVs caused a weak interleukin-1β production in a NLRP3-dependent manner. These findings indicate that  Salmonella  OMV triggers NLRC4 inflammasome activation  via  OMV-associated flagellin in addition to a mild induction of non-canonical inflammasome signaling  via  OMV-bound lipopolysaccharide. Intriguingly, flagellated  Salmonella -derived OMVs induced more rapid inflammasome response than flagellin-deficient  Salmonella  OMV and non-flagellated  Escherichia coli -derived OMVs. Supporting these  in vitro  results,  Nlrc4 -deficient mice showed significantly reduced interleukin-1β production after intraperitoneal challenge with  Salmonella -released OMVs. Taken together, our results here propose that NLRC4 inflammasome machinery is a rapid sensor of bacterial OMV-bound flagellin as a host defense mechanism against bacterial pathogen infection.

Bacterial Outer Membrane Vesicle-Mediated Cytosolic Delivery of Flagellin Triggers Host NLRC4 Canonical Inflammasome Signaling