Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Macrophages utilize Ipaf (a NACHT-leucine-rich repeat family member) to detect Salmonella typhimurium infection.
• Ipaf activation leads to caspase-1 activation and interleukin-1beta secretion.
• The specific Salmonella-derived molecule that activates Ipaf during infection remained unidentified.

Purpose of the Study:

• To identify the Salmonella-derived agonist responsible for activating the Ipaf inflammasome pathway.
• To elucidate the mechanism by which Salmonella flagellin interacts with the host immune system.

Main Methods:

• Investigated the role of bacterial flagellin in activating caspase-1 via Ipaf in macrophages.
• Utilized Salmonella pathogenicity island 1 (SPI-1) and flagellar type III secretion systems (T3SS) in infection models.
• Assessed Ipaf activation following direct introduction of purified flagellin into the macrophage cytoplasm.

Main Results:

• Cytosolic bacterial flagellin was identified as a potent activator of caspase-1 through Ipaf.
• Flagellin-induced Ipaf activation was independent of Toll-like receptor 5 (TLR5).
• Ipaf activation required a functional SPI-1 T3SS but not the flagellar T3SS, and could be triggered by cytoplasmic flagellin.

Conclusions:

• Salmonella flagellin acts as a key agonist for the Ipaf inflammasome pathway.
• The SPI-1 T3SS may facilitate 'promiscuous' flagellin secretion into the host cytoplasm.
• Host immune cells exploit this flagellin secretion to activate potent defense responses against Salmonella infection.