Necrotizing enterocolitis induces T lymphocyte-mediated injury in the developing mammalian brain.
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UNIL restricted access
State: Public
Version: Final published version
License: Not specified
Serval ID
serval:BIB_034C3C918EC7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Necrotizing enterocolitis induces T lymphocyte-mediated injury in the developing mammalian brain.
Journal
Science translational medicine
ISSN
1946-6242 (Electronic)
ISSN-L
1946-6234
Publication state
Published
Issued date
06/01/2021
Peer-reviewed
Oui
Volume
13
Number
575
Pages
eaay6621
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
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 <sup>+</sup> 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 <sup>-/-</sup> recipient mice lacking CD4 <sup>+</sup> 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 <sup>+</sup> T lymphocytes induced microglial activation and myelin loss in the organoids. IFN-γ knockdown in CD4 <sup>+</sup> T cells derived from mice with NEC abrogated the induction of NEC-associated brain injury after adoptive transfer to naïve Rag1 <sup>-/-</sup> 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 <sup>+</sup> T lymphocytes into naïve Rag1 <sup>-/-</sup> 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 <sup>+</sup> T cells, suggesting that early management of intestinal inflammation in children with NEC could improve neurological outcomes.
Pubmed
Create date
25/01/2021 13:24
Last modification date
18/07/2024 6:07