Toll Like Receptor 4 Mediated Lymphocyte Imbalance Induces Nec-Induced Lung Injury

Hongpeng Jia, Chhinder P. Sodhi, Yukihiro Yamaguchi, Peng Lu, Mitchell R. Ladd, Adam Werts, William B. Fulton, Sanxia Wang, Thomas Prindle, David J. Hackam

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants, and is associated with the development of severe lung inflammation. The pathogenesis of NEC-induced lung injury remains unknown, yet infiltrating immune cells may play a role. In support of this possibility, we now show that NEC in mice and humans was associated with the development of profound lung injury that was characterized by an influx of Th17 cells and a reduction in T regulatory lymphocytes (Tregs). Importantly, the adoptive transfer of CD4+ T cells isolated from lungs of mice with NEC into the lungs of immune incompetent mice (Rag1-/- mice) induced profound inflammation in the lung, while the depletion of Tregs exacerbated NEC induced lung injury, demonstrating that imbalance of Th17/Treg in the lung is required for the induction of injury. In seeking to define the mechanisms involved, the selective deletion of toll-like receptor 4 (TLR4) from the Sftpc1 pulmonary epithelial cells reversed lung injury, while TLR4 activation induced the Th17 recruiting chemokine (C-C motif) ligand 25 (CCL25) in the lungs of mice with NEC. Strikingly, the aerosolized inhibition of both CCL25 and TLR4 and the administration of all trans retinoic acid restored Tregs attenuated NEC-induced lung injury. In summary, we show that TLR4 activation in Surfactant protein C-1 (Sftpc1) cells disrupts the Treg/Th17 balance in the lung via CCL25 leading to lung injury after NEC and reveal that inhibition of TLR4 and stabilization of Th17/Treg balance in the neonatal lung may prevent this devastating complication of NEC.

Original languageEnglish (US)
Pages (from-to)215-223
Number of pages9
Issue number2
StatePublished - Aug 1 2019


  • Acute lung injury
  • Th17 cells
  • Treg cells
  • compound 34 (C34)
  • necrotizing enterocolitis
  • toll-like receptor 4 (TLR4)

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine


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