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Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities
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/T(H)17 polarization. In mur...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666196/ https://www.ncbi.nlm.nih.gov/pubmed/33188181 http://dx.doi.org/10.1038/s41467-020-19400-w |
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author | Cho, Steven X. Rudloff, Ina Lao, Jason C. Pang, Merrin A. Goldberg, Rimma Bui, Christine B. McLean, Catriona A. Stock, Magdalena Klassert, Tilman E. Slevogt, Hortense Mangan, Niamh E. Cheng, Wei Fischer, Doris Gfroerer, Stefan Sandhu, Manjeet K. Ngo, Devi Bujotzek, Alexander Lariviere, Laurent Schumacher, Felix Tiefenthaler, Georg Beker, Friederike Collins, Clare Kamlin, C. Omar F. König, Kai Malhotra, Atul Tan, Kenneth Theda, Christiane Veldman, Alex Ellisdon, Andrew M. Whisstock, James C. Berger, Philip J. Nold-Petry, Claudia A. Nold, Marcel F. |
author_facet | Cho, Steven X. Rudloff, Ina Lao, Jason C. Pang, Merrin A. Goldberg, Rimma Bui, Christine B. McLean, Catriona A. Stock, Magdalena Klassert, Tilman E. Slevogt, Hortense Mangan, Niamh E. Cheng, Wei Fischer, Doris Gfroerer, Stefan Sandhu, Manjeet K. Ngo, Devi Bujotzek, Alexander Lariviere, Laurent Schumacher, Felix Tiefenthaler, Georg Beker, Friederike Collins, Clare Kamlin, C. Omar F. König, Kai Malhotra, Atul Tan, Kenneth Theda, Christiane Veldman, Alex Ellisdon, Andrew M. Whisstock, James C. Berger, Philip J. Nold-Petry, Claudia A. Nold, Marcel F. |
author_sort | Cho, Steven X. |
collection | PubMed |
description | 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/T(H)17 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. |
format | Online Article Text |
id | pubmed-7666196 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76661962020-11-17 Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities Cho, Steven X. Rudloff, Ina Lao, Jason C. Pang, Merrin A. Goldberg, Rimma Bui, Christine B. McLean, Catriona A. Stock, Magdalena Klassert, Tilman E. Slevogt, Hortense Mangan, Niamh E. Cheng, Wei Fischer, Doris Gfroerer, Stefan Sandhu, Manjeet K. Ngo, Devi Bujotzek, Alexander Lariviere, Laurent Schumacher, Felix Tiefenthaler, Georg Beker, Friederike Collins, Clare Kamlin, C. Omar F. König, Kai Malhotra, Atul Tan, Kenneth Theda, Christiane Veldman, Alex Ellisdon, Andrew M. Whisstock, James C. Berger, Philip J. Nold-Petry, Claudia A. Nold, Marcel F. Nat Commun Article 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/T(H)17 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. Nature Publishing Group UK 2020-11-13 /pmc/articles/PMC7666196/ /pubmed/33188181 http://dx.doi.org/10.1038/s41467-020-19400-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Cho, Steven X. Rudloff, Ina Lao, Jason C. Pang, Merrin A. Goldberg, Rimma Bui, Christine B. McLean, Catriona A. Stock, Magdalena Klassert, Tilman E. Slevogt, Hortense Mangan, Niamh E. Cheng, Wei Fischer, Doris Gfroerer, Stefan Sandhu, Manjeet K. Ngo, Devi Bujotzek, Alexander Lariviere, Laurent Schumacher, Felix Tiefenthaler, Georg Beker, Friederike Collins, Clare Kamlin, C. Omar F. König, Kai Malhotra, Atul Tan, Kenneth Theda, Christiane Veldman, Alex Ellisdon, Andrew M. Whisstock, James C. Berger, Philip J. Nold-Petry, Claudia A. Nold, Marcel F. Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities |
title | Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities |
title_full | Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities |
title_fullStr | Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities |
title_full_unstemmed | Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities |
title_short | Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities |
title_sort | characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666196/ https://www.ncbi.nlm.nih.gov/pubmed/33188181 http://dx.doi.org/10.1038/s41467-020-19400-w |
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