Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities

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 Cheng, Doris Fischer, Stefan Gfroerer, Manjeet K. Sandhu, Devi Ngo, Alexander Bujotzek, Laurent Lariviere, Felix Schumacher, Georg Tiefenthaler, Friederike Beker, Clare Collins, C. Omar F. Kamlin, Kai König, Atul Malhotra, Kenneth Tan, Christiane Theda, Alex Veldman, Andrew M. Ellisdon, James C. Whisstock, Philip J. Berger, Claudia A. Nold-Petry and Marcel F. Nold ()
Additional contact information
Steven X. Cho: Monash University
Ina Rudloff: Monash University
Jason C. Lao: Monash University
Merrin A. Pang: Monash University
Rimma Goldberg: Monash University
Christine B. Bui: Monash University
Catriona A. McLean: Alfred Hospital
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
Wei Cheng: Beijing United Family Hospital
Doris Fischer: Goethe University Hospital
Stefan Gfroerer: Goethe University Hospital
Manjeet K. Sandhu: Monash University
Devi Ngo: Monash University
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
Clare Collins: Neonatal Services, Mercy Hospital for Women
C. Omar F. Kamlin: Royal Women’s Hospital
Kai König: Medicum Wesemlin, Department of Paediatrics
Atul Malhotra: Monash University
Kenneth Tan: Monash University
Christiane Theda: Royal Women’s Hospital
Alex Veldman: Hudson Institute of Medical Research
Andrew M. Ellisdon: Monash University
James C. Whisstock: Monash University
Philip J. Berger: Monash University
Claudia A. Nold-Petry: Monash University
Marcel F. Nold: Monash University

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19400-w

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