Necrotizing enterocolitis induces T lymphocyte–mediated injury in the developing mammalian brain

Qinjie Zhou, Diego F. Niño, Yukihiro Yamaguchi, Sanxia Wang, William B. Fulton, Hongpeng Jia, Peng Lu, Thomas Prindle, David Pamies, Meaghan Morris, Liam L. Chen, Chhinder P. Sodhi, David J. Hackam

Research output: Contribution to journalArticlepeer-review

Abstract

Necrotizing enterocolitis (NEC) causes acute intestinal necrosis in premature infants and is associated with severe neurological impairment. In NEC, Toll-like receptor 4 is activated in the intestinal epithelium, and NEC-associated brain injury is characterized by microglial activation and white matter loss through mechanisms that remain unclear. We now show that the brains of mice and humans with NEC contained CD4+ T lymphocytes that were required for the development of brain injury. Inhibition of T lymphocyte influx into the brains of neonatal mice with NEC reduced inflammation and prevented myelin loss. Adoptive intracerebroventricular delivery of gut T lymphocytes from mice with NEC into Rag1−/− recipient mice lacking CD4+ T cells resulted in brain injury. Brain organoids derived from mice with or without NEC and from human neuronal progenitor cells revealed that IFN-γ release by CD4+ T lymphocytes induced microglial activation and myelin loss in the organoids. IFN-γ knockdown in CD4+ T cells derived from mice with NEC abrogated the induction of NEC-associated brain injury after adoptive transfer to naïve Rag1−/− recipient mice. T cell receptor sequencing revealed that NEC mouse brain-derived T lymphocytes shared homology with gut T lymphocytes from NEC mice. Intraperitoneal injection of NEC gut-derived CD4+ T lymphocytes into naïve Rag1−/− recipient mice induced brain injury, suggesting that gut-derived T lymphocytes could mediate neuroinflammation in NEC. These findings indicate that NEC-associated brain injury may be induced by gut-derived IFN-γ–releasing CD4+ T cells, suggesting that early management of intestinal inflammation in children with NEC could improve neurological outcomes.

Original languageEnglish (US)
Article numbereaay6621
JournalScience Translational Medicine
Volume13
Issue number575
DOIs
StatePublished - Jan 6 2021
Externally publishedYes

Bibliographical note

Funding Information:
D.J.H. was funded by grants RO1DK117186, RO1DK121824, and RO1GM078238 from the NIH. H.J. was funded by grants RO1AI148446 and R21AI49321.

Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved;

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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