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 TiefenthalerFriederike 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, Marcel F. Nold

Research output: Contribution to journalArticleResearchpeer-review

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 NKp46RORγt+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.

Original languageEnglish
Article number5794
Number of pages19
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 2020

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