Dataset Information

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

ABSTRACT:

Introduction

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.

Objectives

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

Methods

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.

Results

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.

Conclusion

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.

SUBMITTER: Guo S

PROVIDER: S-EPMC9936422 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

CBS-H<sub>2</sub>S axis preserves the intestinal barrier function by inhibiting COX-2 through sulfhydrating human antigen R in colitis.

Guo Shihao S Huang Zhihao Z Zhu Jing J Yue Taohua T Wang Xin X Pan Yisheng Y Bu Dingfang D Liu Yucun Y Wang Pengyuan P Chen Shanwen S

Journal of advanced research 20220317

<h4>Introduction</h4>Lipopolysaccharide (LPS) causes lesions of the epithelial barrier, which allows translocation of pathogens from the intestinal lumen to the host's circulation. Hydrogen sulfide (H<sub>2</sub>S) regulates multiple physiological and pathological processes in colonic epithelial tissue, and CBS-H<sub>2</sub>S axis involved in multiple gastrointestinal disorder. However, the mechanism underlying the effect of the CBS-H<sub>2</sub>S axis on the intestinal and systemic inflammation ...[more]

PMID: 36725190

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Project description:OBJECTIVES:The intestinal epithelium compartmentalizes the sterile bloodstream and the commensal bacteria in the gut. Accumulating evidence suggests that this barrier is impaired in sepsis, aggravating systemic inflammation. Previous studies reported that cathelicidin is differentially expressed in various tissues in sepsis. However, its role in sepsis-induced intestinal barrier dysfunction has not been investigated. DESIGN:To examine the role of cathelicidin in polymicrobial sepsis, cathelicidin wild-(Cnlp+/+) and knockout (Cnlp-/-) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical, immunological, and transcriptomic analyses in the ileal tissues. We also evaluated the prophylactic and therapeutic efficacies of vitamin D3 (an inducer of endogenous cathelicidin) in the CLP-induced murine polymicrobial sepsis model. RESULTS:The ileal expression of cathelicidin was increased by three-fold after CLP, peaking at 4?h. Knockout of Cnlp significantly increased 7-day mortality and was associated with a higher murine sepsis score. Alcian-blue staining revealed a reduced number of mucin-positive goblet cells, accompanied by reduced mucin expression. Increased number of apoptotic cells and cleavage of caspase-3 were observed. Cnlp deletion increased intestinal permeability to 4kD fluorescein-labeled dextran and reduced the expression of tight junction proteins claudin-1 and occludin. Notably, circulating bacterial DNA load increased more than two-fold. Transcriptome analysis revealed upregulation of cytokine/inflammatory pathway. Depletion of Cnlp induced more M1 macrophages and neutrophils compared with the wild-type mice after CLP. Mice pre-treated with cholecalciferol (an inactive form of vitamin D3) or treated with 1alpha, 25-dihydroxyvitamin D3 (an active form of VD3) had decreased 7-day mortality and significantly less severe symptoms. Intriguingly, the administration of cholecalciferol after CLP led to worsened 7-day mortality and the associated symptoms. CONCLUSIONS:Endogenous cathelicidin promotes intestinal barrier integrity accompanied by modulating the infiltration of neutrophils and macrophages in polymicrobial sepsis. Our data suggested that 1alpha, 25-dihydroxyvitamin D3 but not cholecalciferol is a potential therapeutic agent for treating sepsis.

Dataset Information

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

Introduction

Objectives

Methods

Results

Conclusion

Publications

CBS-H<sub>2</sub>S axis preserves the intestinal barrier function by inhibiting COX-2 through sulfhydrating human antigen R in colitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Introduction

Objectives

Methods

Results

Conclusion

Publications

CBS-H<sub>2</sub>S axis preserves the intestinal barrier function by inhibiting COX-2 through sulfhydrating human antigen R in colitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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