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Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis

The Journal of clinical investigation, 2016-02, Vol.126 (2), p.495-508 [Peer Reviewed Journal]

COPYRIGHT 2016 American Society for Clinical Investigation ;COPYRIGHT 2016 American Society for Clinical Investigation ;Copyright American Society for Clinical Investigation Feb 2016 ;Copyright © 2016, American Society for Clinical Investigation 2016 American Society for Clinical Investigation ;ISSN: 0021-9738 ;EISSN: 1558-8238 ;DOI: 10.1172/jci83356 ;PMID: 26690704

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Title:
Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis
Author: Egan, Charlotte E ; Sodhi, Chhinder P ; Good, Misty ; Lin, Joyce ; Jia, Hongpeng ; Yamaguchi, Yukihiro ; Lu, Peng ; Ma, Congrong ; Branca, Maria F ; Weyandt, Samantha ; Fulton, William B ; Niño, Diego F ; Prindle, Jr, Thomas ; Ozolek, John A ; Hackam, David J
Subjects: Animals ; Comparative analysis ; Development and progression ; Disease susceptibility ; Enterocolitis, Necrotizing - diet therapy ; Enterocolitis, Necrotizing - genetics ; Enterocolitis, Necrotizing - immunology ; Enterocolitis, Necrotizing - pathology ; Enterocolitis, Neonatal necrotizing ; Enterocolitis, Pseudomembranous ; Enterocytes - immunology ; Enterocytes - pathology ; Experiments ; Gene expression ; Genetic aspects ; Health aspects ; Humans ; Infant, Newborn ; Infant, Newborn, Diseases - diet therapy ; Infant, Newborn, Diseases - genetics ; Infant, Newborn, Diseases - immunology ; Infant, Newborn, Diseases - pathology ; Laboratory animals ; Lymphocytes ; Mice ; Mice, Knockout ; Mortality ; Ostomy ; Pathogenesis ; Rodents ; Small intestine ; Studies ; T-Lymphocytes, Regulatory - immunology ; T-Lymphocytes, Regulatory - pathology ; Th17 Cells - immunology ; Th17 Cells - pathology ; Tight Junctions - genetics ; Tight Junctions - immunology ; Toll-Like Receptor 4 - genetics ; Toll-Like Receptor 4 - immunology ; Toll-like receptors
Is Part Of: The Journal of clinical investigation, 2016-02, Vol.126 (2), p.495-508
Description: 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 (Rag1–/–) mice were protected from NEC and transfer of intestinal lymphocytes from NEC mice into naive mice induced intestinal inflammation. The intestinal expression of the lipopolysaccharide receptor TLR4, which is higher in the premature compared with full-term human and mouse intestine, is required for lymphocyte influx through TLR4-mediated upregulation of CCR9/CCL25 signaling. TLR4 also mediates a STAT3-dependent polarization toward increased proinflammatory CD3+CD4+IL-17+ and reduced tolerogenic Foxp3+ Treg lymphocytes (Tregs). Th17 lymphocytes were required for NEC development, as inhibition of STAT3 or IL-17 receptor signaling attenuated NEC in mice, while IL-17 release impaired enterocyte tight junctions, increased enterocyte apoptosis, and reduced enterocyte proliferation, leading to NEC. Importantly, TLR4-dependent Th17 polarization could be reversed by the enteral administration of retinoic acid, which induced Tregs and decreased NEC severity. These findings identify an important role for proinflammatory lymphocytes in NEC development via intestinal epithelial TLR4 that could be reversed through dietary modification.
Publisher: United States: American Society for Clinical Investigation
Language: English
Identifier: ISSN: 0021-9738
EISSN: 1558-8238
DOI: 10.1172/jci83356
PMID: 26690704
Source: PubMed Central (Open access)
GFMER Free Medical Journals
MEDLINE
ProQuest Central

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Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis

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