Insight into neonatal necrotizing enterocolitis
Necrotizing enterocolitis (NEC) is a serious inflammatory disease that primarily affects premature infants and is characterized by immune cell infiltration into the intestinal mucosa, disruption of the intestinal barrier, and a high incidence of systemic sepsis. Therapeutic options for NEC are limited and the drivers of NEC pathogenesis are incompletely understood. Charlotte Egan and colleagues at the Children’s Hospital of Pittsburgh evaluated the immune cell population in the intestines newborn infants and mice with or without NEC and determined that NEC development is associated with a lymphocyte-rich infiltrate that is characterized by an induction of Th17 cells and a reduction of regulatory T cells (Tregs). The presence of lymphocytes was required for the development of NEC, as Rag-/- mice were protected from NEC development; however, adoptive transfer of naïve CD4+ T cells into these mice prior to NEC induction restored NEC susceptibility. TLR4 is elevated in the intestines of premature infants and mice, and animals lacking TLR4 in the intestinal epithelium are protected from NEC. The authors determined that TLR4-dependent release of CCL25 mediates lymphocyte recruitment to the gut. Moreover, persistent TLR4 signaling skewed the tolerogenic Treg population toward an injurious Th17 subset via STAT3-dependent polarization. Th17 cells were required for NEC development, as targeting STAT3 or IL-17 signaling reduced NEC development in mice. Additionally, enteral administration of retinoic acid reversed Th17 polarization, elevated Tregs, and reduced NEC severity. Together, these results provide important insight into the drivers of NEC and suggest retinoic acid be further explored as a potential treatment for NEC. The accompanying confocal micrograph shows the terminal ileum of a Rag-/- animal that had been reconstituted with donor CD4+ T cells prior to induction of NEC. Note the damage (mucosal 3-nitrotyrosine, red) to the intestinal epithelium (E-cadherin, green), which is characteristic of NEC. Nuclei stained blue with DAPI.
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Abstract
The nature and role of the intestinal leukocytes in necrotizing enterocolitis (NEC), a severe disease affecting premature infants, remain unknown. We now show that the intestine in mouse and human NEC is rich in lymphocytes that are required for NEC development, as recombination activating gene 1–deficient (
Authors
Charlotte E. Egan, Chhinder P. Sodhi, Misty Good, Joyce Lin, Hongpeng Jia, Yukihiro Yamaguchi, Peng Lu, Congrong Ma, Maria F. Branca, Samantha Weyandt, William B. Fulton, Diego F. Niño, Thomas Prindle Jr., John A. Ozolek, David J. Hackam
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ISSN: 0021-9738 (print), 1558-8238 (online)