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Critical Care
Published in: Critical Care 1/2020

01-12-2020 | Septicemia | Research

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Authors: Jeffery Ho, Hung Chan, Yonghao Liang, Xiaodong Liu, Lin Zhang, Qing Li, Yuchen Zhang, Judeng Zeng, Felix N. Ugwu, Idy H. T. Ho, Wei Hu, Johnny C. W. Yau, Sunny H. Wong, Wai Tat Wong, Lowell Ling, Chi H. Cho, Richard L. Gallo, Tony Gin, Gary Tse, Jun Yu, Matthew T. V. Chan, Czarina C. H. Leung, William K. K. Wu

Published in: Critical Care | Issue 1/2020

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Abstract

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.
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Metadata
Title
Cathelicidin preserves intestinal barrier function in polymicrobial sepsis
Authors
Jeffery Ho
Hung Chan
Yonghao Liang
Xiaodong Liu
Lin Zhang
Qing Li
Yuchen Zhang
Judeng Zeng
Felix N. Ugwu
Idy H. T. Ho
Wei Hu
Johnny C. W. Yau
Sunny H. Wong
Wai Tat Wong
Lowell Ling
Chi H. Cho
Richard L. Gallo
Tony Gin
Gary Tse
Jun Yu
Matthew T. V. Chan
Czarina C. H. Leung
William K. K. Wu
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2020
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-020-2754-5

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