Cathelicidin preserves intestinal barrier function in polymicrobial sepsis
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
Affiliations
Jeffery Ho
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Hung Chan
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Yonghao Liang
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Xiaodong Liu
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Lin Zhang
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Qing Li
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Yuchen Zhang
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Judeng Zeng
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Felix N. Ugwu
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Idy H. T. Ho
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Wei Hu
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Johnny C. W. Yau
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Sunny H. Wong
Department of Medicine and Therapeutics, The Chinese University of Hong Kong
Wai Tat Wong
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Lowell Ling
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Chi H. Cho
Laboratory of Molecular Pharmacology, School of Pharmacy, Southwest Medical University
Richard L. Gallo
Department of Dermatology, The University of California
Tony Gin
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Gary Tse
Department of Medicine and Therapeutics, The Chinese University of Hong Kong
Jun Yu
State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, and Centre for Gut Microbiota Research, The Chinese University of Hong Kong
Matthew T. V. Chan
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
Czarina C. H. Leung
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
William K. K. Wu
Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong
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.
