Role of nucleotide binding oligomerization domain-like receptor protein 3 inflammasome in stress-induced gastric injury

Background and Aim: The inflammasomes promote pro-caspase-1 cleavage, leading to processing of pro-interleukin (IL)-1 beta into its mature form. We investigated the role of the IL-1 beta and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in gastric injury in mice receiving water-immersion restraint stress (WIRS), focusing on the cyclooxygenase (COX)-2/prostaglandin (PG) E-2 axis. Methods: To induce gastric injury, the mice were placed in a restraint cage and immersed in the water bath to the level of the xiphoid process. Protein levels of mature caspase-1 and IL-1 beta were assessed by western blotting. Results: Water-immersion restraint stress induced gastric injury with increase in IL-1 beta expression by activation of NLRP3 inflammasome. Exogenous IL-1 beta attenuated the injury, whereas anti-IL-1 beta neutralizing antibody and IL-1 beta receptor antibody aggravated it. NLRP3(-/-) and caspase-1(-/-) mice enhanced the injury with reducing of mature IL-1 beta, and this aggravation was reduced by exogenous IL-1 beta supplementation. Toll-like receptor 4(-/-) mice were hyporesponsive to WIRS in terms of mature IL-1 beta production. Rabeprazole attenuated the injury with preventing inflammasome activation. WIRS injured the stomach with promotion of COX-2 mRNA and PGE(2) production, and exogenous IL-1 beta enhanced these molecules, while IL-1 beta immunoneutralization exerted opposite effect. PGE(2) supplementation abolished the hypersensitivity in NLRP3(-/-) and caspase-1(-/-) mice through negative regulation of inflammatory cytokines. Conclusion: These results suggest that NLRP3 inflammasome-derived IL-1 beta plays a protective role in stress-induced gastric injury via activation of the COX-2/PGE(2) axis. Toll-like receptor 4 signaling and gastric acid may be involved in NLRP3 inflammasome activation.

Automated summary

The study revealed that NLRP3 inflammasome-derived IL-1 beta plays a protective role in stress-induced gastric injury through activation of the COX-2/PGE(2) axis. Toll-like receptor 4 signaling and gastric acid may be involved in NLRP3 inflammasome activation.