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

• DOI: 10.1016/j.jare.2022.03.010
• Publication Date: 2022-03-17T02:18:43Z
• Authors: Shihao Guo; Zhihao Huang; Jing Zhu; Taohua Yue; Xin Wang; Yisheng Pan; Dingfang Bu; Yucun Liu; Pengyuan Wang; Shanwen Chen
• Keywords: Lipopolysaccharides; Inflammation; Medicine (General); 0303 health sciences; Science (General); H2S; COX-2; Colitis; Q1-390; Mice; 03 medical and health sciences; R5-920; Cyclooxygenase 2; HuR; Humans; Animals; Sulfhydration; Original Article; Hydrogen Sulfide

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.