Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities
Open Access
- 13 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-19
- https://doi.org/10.1038/s41467-020-19400-w
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.Funding Information
- Department of Health | National Health and Medical Research Council (1043845)
This publication has 88 references indexed in Scilit:
- Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) InhibitorsPLOS ONE, 2013
- The Transcription Factor GATA-3 Controls Cell Fate and Maintenance of Type 2 Innate Lymphoid CellsImmunity, 2012
- Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platformsThe ISME Journal, 2012
- Interleukin 37 expression protects mice from colitisProceedings of the National Academy of Sciences of the United States of America, 2011
- IL-23–responsive innate lymphoid cells are increased in inflammatory bowel diseaseThe Journal of Experimental Medicine, 2011
- The age of necrotizing enterocolitis onset: an application of Sartwell's incubation period modelJournal of Perinatology, 2011
- Generation of pathogenic TH17 cells in the absence of TGF-β signallingNature, 2010
- IL-37 is a fundamental inhibitor of innate immunityNature Immunology, 2010
- QIIME allows analysis of high-throughput community sequencing dataNature Methods, 2010
- 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitisThe ISME Journal, 2009