Abstract
Background
Necrotizing enterocolitis (NEC), an intestinal inflammatory disease affecting premature infants, is associated with low regulatory T (Treg) to effector T (Teff) cell ratios. We recently demonstrated that heme oxygenase-1 (HO-1) deficiency leads to increased NEC development. Here, we investigated the effects of HO-1 on T-cell proportions in a murine NEC-like injury model.
Methods
Intestinal injury was induced in 7-d-old wild-type (WT) or HO-1 heterozygous (HO-1 Het) pups by formula-feeding every 4 h for 24–78 h by oral gavage and exposures to 5%O2. Controls remained breastfed. HO-1 was induced in WT pups by administering heme preinjury induction. Lamina propria T cells were identified by flow cytometry. For adoptive transfer studies, WT splenic/thymic Tregs were injected intraperitoneally into HO-1 Het pups 12–24 h preinduction.
Results
Het mice showed increased intestinal injury and decreased Treg/Teff ratios. Genes for pattern recognition (Toll-like receptor-4, C-reactive protein, MyD88) and neutrophil recruitment increased in Het pups after NEC induction. Inducing intestinal HO-1 decreased NEC scores and incidence, and increased Treg/Teff ratios. Moreover, adoptive transfer of Tregs from WT to HO-1 Het pups decreased NEC scores and incidence and restored Treg/Teff ratios.
Conclusion
HO-1 can change Treg proportions in the lamina propria of young mice under inflammatory conditions, which might, in part, confer intestinal protection.
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Acknowledgements
We thank Hendrik J. Vreman, Department of Pediatrics, Stanford University, for providing the hypoxia chamber; Norm Cyr, Digital Imaging Specialist, from the Department of Pathology, Stanford University, for assisting with the high quality histological images; and Pauline Chu, from the Department of Comparative Medicine, Stanford University, for her technical expertise in tissue sectioning and H&E staining. We also thank the staff at the Stanford Shared Fluorescence-Activated Cell Sorting (FACS) Facility for their invaluable help in starting this project and Karl G. Sylvester (Department of Pediatric Surgery, Stanford University) for his critical review of the manuscript.
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Schulz, S., Chisholm, K., Zhao, H. et al. Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation. Pediatr Res 77, 640–648 (2015). https://doi.org/10.1038/pr.2015.22
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DOI: https://doi.org/10.1038/pr.2015.22
