ArticleThe Journal of clinical investigation2016
Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 170 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
170 citing papers in PubMed, 1 synthesis or guideline pooled it, 230 citations in OpenAlex.
- Enteral Feeding Interventions in the Prevention of Necrotizing Enterocolitis: A Systematic Review of Experimental and Clinical Studies.Nutrients · 2021Pooled it
- Association of single nucleotide polymorphisms of IL23R and IL17 with necrotizing enterocolitis in premature infants.Molecular and cellular biochemistry · 2017Trial
- The gut-brain ConNECtion: exploring the developmental impact of necrotizing enterocolitis on the neonatal brain.Pediatric research · 2026Review
- Deciphering the TLR4 and NLRP3 Inflammasome Crosstalk for Therapeutic Restoration of Intestinal and Systemic Immunity.Digestive diseases and sciences · 2026Review
- RPS29 as a potential early diagnostic biomarker for necrotizing enterocolitis: validation from transcriptomic and proteomic cohorts.Translational pediatrics · 2026Article
- Diagnosis and Staging of Necrotizing Enterocolitis: Current Controversies and a Phenotype-Based Framework.Children (Basel, Switzerland) · 2026Review
- Urolithin A attenuates inflammation and enhances barrier integrity in an experimental NEC-in-a-Dish model.Pediatric research · 2026Article
- Blockade of NKp46⁻ CCR6⁻ ILC3 autophagy protects against necrotizing enterocolitis by restoring energy metabolism balance in mice.Nature communications · 2026Article
- Necrotizing enterocolitis.Nature reviews. Disease primers · 2026Review
- Sildenafil pretreatment attenuates apoptosis and intestinal injury in a hypoxia-ischemia-induced NEC-like rat model.Scientific reports · 2026Article
- [Clinical significance of neutrophil chemokines in intestinal tissue and related receptor expression in peripheral blood in neonatal necrotizing enterocolitis].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2026Article
- Biofilm probiotics for NEC: promise, pitfalls, and pathways to translation.Pediatric research · 2026Article
- The role of myeloid cells in the pathogenesis of necrotizing enterocolitis; a scoping review.Frontiers in pediatrics · 2026Review
- Neurodevelopmental impairment in infants with necrotizing enterocolitis: a comprehensive review of mechanisms, outcomes, and emerging strategies.World journal of pediatric surgery · 2026Review
- Vitamins as modulators of neonatal intestinal injury.Frontiers in nutrition · 2026Review
- Pathogenesis of necrotizing enterocolitis: mechanisms and mediators.World journal of pediatric surgery · 2026Review
- L-cystine alleviates necrotizing enterocolitis by regulating ferroptosis and Th17 cell differentiation via the IL-6/STAT3 pathway.Communications biology · 2025Article
- Digging deeper into necrotizing enterocolitis: bridging clinical, microbial, and molecular perspectives.Gut microbes · 2025Review
- IL-27Ra promotes the progression of neonatal necrotizing enterocolitis.Scientific reports · 2025Article
- The microbiome's hidden influence: preclinical insights into inflammatory responses in necrotizing enterocolitis.Seminars in immunopathology · 2025Review
110 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
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 (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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.