Intestinal NF-κB pathway-mediated pyroptosis contributes to endotoxemia-induced intestinal injury

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Pyroptosis is crucial for innate immunity and pathogen defense.
• Endotoxemia triggers a severe inflammatory response, but its effect on intestinal cells is unclear.
• NF-κB signaling is implicated in inflammatory processes.

Purpose of the Study:

• To investigate the role of NF-κB p65-mediated pyroptosis in endotoxemia-induced intestinal epithelial cell (IEC) injury.
• To explore the involvement of endoplasmic reticulum (ER) stress in this process.
• To assess potential therapeutic strategies targeting pyroptosis in endotoxemia.

Main Methods:

• Utilized mice with NF-κB p65 deletion in IECs (p65IEC-KO) and wild-type (WT) littermates.
• Administered lipopolysaccharide (LPS) to induce endotoxemia.
• Evaluated intestinal morphology, pyroptosis markers, permeability, inflammation, ER stress, and survival rates.

Main Results:

• LPS induced pyroptosis in WT mice's IECs, which was reduced in p65IEC-KO mice.
• Endotoxemia caused intestinal damage (shortened villi/crypts, increased permeability, inflammation) and reduced survival in WT mice.
• These negative effects were significantly improved in p65IEC-KO mice, with downregulated ER stress.

Conclusions:

• NF-κB p65-mediated pyroptosis contributes to intestinal epithelial cell injury during endotoxemia.
• ER stress is a key mediator in NF-κB-driven pyroptosis and subsequent intestinal damage.
• Targeting NF-κB-mediated pyroptosis and ER stress presents a potential therapeutic avenue for endotoxemia-induced intestinal injury.