CBS-H₂S axis preserves the intestinal barrier function by inhibiting COX-2 through sulfhydrating human antigen R in...

Lipopolysaccharide (LPS) causes lesions of the epithelial barrier, which allows translocation of pathogens from the intestinal lumen to the host's circulation. Hydrogen sulfide (H₂S) regulates multiple physiological and pathological processes in colonic epithelial tissue, and CBS-H₂S axis involved in multiple gastrointestinal disorder. However, the mechanism underlying the effect of the CBS-H₂S axis on the intestinal and systemic inflammation in colitis remains to be illustrated.

To investigate the effect of CBS-H₂S axis on the intestinal and systematic inflammation related injuries in LPS induced colitis and the underlying mechanisms.

Wild type and CBS^-/+ mice were used to evaluate the effect of endogenous and exogenous H₂S on LPS-induced colitis in vivo. Cytokine quantitative antibody array, western blot and real-time PCR were applied to detect the key cytokines in the mechanism of action. Biotin switch of S-sulfhydration, CRISPR/Cas9 mediated knockout, immunofluorescence and ActD chase assay were used in the in vitro experiment to further clarify the molecular mechanisms.

H₂S significantly alleviated the symptoms of LPS-induced colitis in vivo and attenuated the increase of COX-2 expression. The sulfhydrated HuR increased when CBS express normally or GYY4137 was administered. While after knocking kown CBS, the expression of COX-2 in mice colon increased significantly, and the sulfhydration level of HuR decreased. The results in vitro illustrated that HuR can increase the stability of COX-2 mRNA, and the decrease of COX-2 were due to increased sulfhydration of HuR rather than the reduction of total HuR levels.

These results indicated that CBS-H₂S axis played an important role in protecting intestinal barrier function in colitis. CBS-H₂S axis increases the sulfhydration level of HuR, by which reduces the binding of HuR with COX-2 mRNA and inhibited the expression of COX-2.