Jungmin Yang: Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Inhwa Hwang: Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Eunju Lee: Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Sung Jae Shin: Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
Eun-Jin Lee: Department of Life Sciences, Korea University, Seoul, South Korea.
Joon Haeng Rhee: Department of Microbiology, Clinical Vaccine R&D Center, Chonnam National University Medical School, Gwangju, South Korea.
Je-Wook Yu: Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
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 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 flagellin delivery to the cytoplasm of host cells. -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 OMV-induced inflammasome response. Flagellated -released OMVs consistently promoted robust NLRC4 inflammasome activation, while non-flagellated -released OMVs induced NLRC4-independent non-canonical inflammasome activation leading to NLRP3-mediated interleukin-1β secretion. Flagellin-deficient OMVs caused a weak interleukin-1β production in a NLRP3-dependent manner. These findings indicate that OMV triggers NLRC4 inflammasome activation OMV-associated flagellin in addition to a mild induction of non-canonical inflammasome signaling OMV-bound lipopolysaccharide. Intriguingly, flagellated -derived OMVs induced more rapid inflammasome response than flagellin-deficient OMV and non-flagellated -derived OMVs. Supporting these results, -deficient mice showed significantly reduced interleukin-1β production after intraperitoneal challenge with -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.
