Inflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Lipopolysaccharide (LPS), a Gram-negative bacterial cell wall component, triggers inflammatory responses and sepsis via caspase-11 activation.
• Host guanylate binding proteins (GBPs) are known to promote caspase-11 activation in vitro, but their in vivo role in LPS-mediated sepsis is unclear.
• Bacteria release LPS as free aggregates or within outer membrane vesicles (OMVs), which deliver LPS into host cells.

Purpose of the Study:

• To investigate the in vivo role of host guanylate binding proteins (GBPs) in lipopolysaccharide (LPS)-mediated sepsis.
• To determine if GBPs are required for caspase-11 activation by free LPS and outer membrane vesicles (OMVs) in vivo.
• To elucidate the mechanism by which GBPs regulate inflammation and sepsis induced by Gram-negative bacterial components.

Main Methods:

• Mice were injected with either free lipopolysaccharide (LPS) or purified outer membrane vesicles (OMVs) from Escherichia coli.
• Inflammatory responses, pyroptotic cell death, and cytokine secretion (IL-1β, IL-18) were assessed in vivo and in macrophages lacking GBP2.
• Caspase-11 activation was monitored following exposure to LPS and OMVs.

Main Results:

• Guanylate binding proteins (GBPs) were found to control inflammation and sepsis in mice challenged with free LPS or OMVs.
• Macrophages deficient in GBP2 failed to induce pyroptosis and secrete IL-1β and IL-18 upon exposure to OMVs.
• GBPs are essential for caspase-11 activation in vivo by both free LPS and OMVs.

Conclusions:

• GBPs play a critical role in regulating host inflammatory responses and sepsis induced by Gram-negative bacterial components.
• GBPs are required for the processing of outer membrane vesicles (OMVs) by macrophages and potentially circulating free LPS by other cell types to activate caspase-11 in vivo.
• The discovery of GBPs as regulators of OMV-mediated inflammation offers insights into host defense mechanisms and potential therapeutic strategies against bacterial infections.