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Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities

Author

Listed:
  • Steven X. Cho

    (Monash University
    Hudson Institute of Medical Research
    Hokkaido University Graduate School of Medicine)

  • Ina Rudloff

    (Monash University
    Hudson Institute of Medical Research)

  • Jason C. Lao

    (Monash University
    Hudson Institute of Medical Research)

  • Merrin A. Pang

    (Monash University
    Hudson Institute of Medical Research)

  • Rimma Goldberg

    (Monash University
    Hudson Institute of Medical Research
    Monash University
    Monash Health)

  • Christine B. Bui

    (Monash University
    Hudson Institute of Medical Research)

  • Catriona A. McLean

    (Alfred Hospital
    Monash University)

  • Magdalena Stock

    (ZIK Septomics, Jena University Hospital)

  • Tilman E. Klassert

    (ZIK Septomics, Jena University Hospital)

  • Hortense Slevogt

    (ZIK Septomics, Jena University Hospital)

  • Niamh E. Mangan

    (Monash University
    Hudson Institute of Medical Research)

  • Wei Cheng

    (Beijing United Family Hospital
    Capital Institute of Pediatrics)

  • Doris Fischer

    (Goethe University Hospital
    St. Vincenz Hospital)

  • Stefan Gfroerer

    (Goethe University Hospital
    Helios Clinic Berlin-Buch)

  • Manjeet K. Sandhu

    (Monash University
    Hudson Institute of Medical Research
    Monash Health)

  • Devi Ngo

    (Monash University
    Hudson Institute of Medical Research)

  • Alexander Bujotzek

    (Roche Innovation Center Munich)

  • Laurent Lariviere

    (Roche Innovation Center Munich)

  • Felix Schumacher

    (Roche Innovation Center Munich)

  • Georg Tiefenthaler

    (Roche Innovation Center Munich)

  • Friederike Beker

    (University of Queensland
    Neonatal Services, Mercy Hospital for Women)

  • Clare Collins

    (Neonatal Services, Mercy Hospital for Women
    Joan Kirner Women’s & Children’s, Sunshine Hospital)

  • C. Omar F. Kamlin

    (Royal Women’s Hospital
    University of Melbourne
    Murdoch Children’s Research Institute)

  • Kai König

    (Medicum Wesemlin, Department of Paediatrics)

  • Atul Malhotra

    (Monash University
    Hudson Institute of Medical Research
    Monash Newborn, Monash Children’s Hospital)

  • Kenneth Tan

    (Monash University
    Hudson Institute of Medical Research
    Monash Newborn, Monash Children’s Hospital)

  • Christiane Theda

    (Royal Women’s Hospital
    University of Melbourne
    Murdoch Children’s Research Institute)

  • Alex Veldman

    (Hudson Institute of Medical Research
    St. Vincenz Hospital
    Liebig University Hospital)

  • Andrew M. Ellisdon

    (Monash University)

  • James C. Whisstock

    (Monash University
    Monash University)

  • Philip J. Berger

    (Monash University
    Hudson Institute of Medical Research)

  • Claudia A. Nold-Petry

    (Monash University
    Hudson Institute of Medical Research)

  • Marcel F. Nold

    (Monash University
    Hudson Institute of Medical Research
    Monash Newborn, Monash Children’s Hospital)

Abstract

Necrotizing enterocolitis (NEC) is a severe, currently untreatable intestinal disease that predominantly affects preterm infants and is driven by poorly characterized inflammatory pathways. Here, human and murine NEC intestines exhibit an unexpected predominance of type 3/TH17 polarization. In murine NEC, pro-inflammatory type 3 NKp46−RORγt+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORγt+ ILC3 are obliterated. Both species exhibit dysregulation of intestinal TLR repertoires, with TLR4 and TLR8 increased, but TLR5-7 and TLR9-12 reduced. Transgenic IL-37 effectively protects mice from intestinal injury and mortality, whilst exogenous IL-37 is only modestly efficacious. Mechanistically, IL-37 favorably modulates immune homeostasis, TLR repertoires and microbial diversity. Moreover, IL-37 and its receptor IL-1R8 are reduced in human NEC epithelia, and IL-37 is lower in blood monocytes from infants with NEC and/or lower birthweight. Our results on NEC pathomechanisms thus implicate type 3 cytokines, TLRs and IL-37 as potential targets for novel NEC therapies.

Suggested Citation

  • Steven X. Cho & Ina Rudloff & Jason C. Lao & Merrin A. Pang & Rimma Goldberg & Christine B. Bui & Catriona A. McLean & Magdalena Stock & Tilman E. Klassert & Hortense Slevogt & Niamh E. Mangan & Wei C, 2020. "Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19400-w
    DOI: 10.1038/s41467-020-19400-w
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