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https://repository.monashhealth.org/monashhealthjspui/handle/1/28976| Title: | Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities. | Authors: | Ngo D.;McLean C.A.;Stock M.;Klassert T.E.;Slevogt H.;Mangan N.E.;Cheng W.;Fischer D.;Gfroerer S.;Sandhu M.K.;Bui C.B.;Bujotzek A.;Lariviere L.;Schumacher F.;Tiefenthaler G.;Beker F.;Collins C.;Kamlin C.O.F.;Konig K.;Malhotra A. ;Theda C.;Veldman A.;Ellisdon A.M.;Whisstock J.C.;Berger P.J.;Nold M.F.;Nold-Petry C.A. ;Tan K. ;Cho S.X.;Rudloff I.;Lao J.C.;Pang M.A.;Goldberg R. | Institution: | (Cho, Rudloff, Lao, Pang, Goldberg, Bui, Sandhu, Ngo, Malhotra, Tan, Berger, Nold-Petry, Nold) Department of Paediatrics, Monash University, Melbourne, VIC, Australia (Cho, Rudloff, Lao, Pang, Goldberg, Bui, Sandhu, Ngo, Malhotra, Tan, Veldman, Berger, Nold-Petry, Nold) Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia (Cho) Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Goldberg) Department of Medicine, Monash University, Melbourne, VIC, Australia (Goldberg, Sandhu) Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia (McLean) Department of Anatomical Pathology, Alfred Hospital, Melbourne, VIC, Australia (McLean) Central Clinical School, Monash University, Melbourne, VIC, Australia (Stock, Klassert, Slevogt) ZIK Septomics, Jena University Hospital, Jena, Germany (Mangan) Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia (Mangan) Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia (Cheng) Department of Surgery, Beijing United Family Hospital, Beijing, China (Cheng) Capital Institute of Pediatrics, Beijing, China (Fischer) Department of Pediatrics, Goethe University Hospital, Frankfurt, Germany (Fischer, Veldman) Department of Pediatrics, St. Vincenz Hospital, Limburg, Germany (Gfroerer) Department of Pediatric Surgery, Goethe University Hospital, Frankfurt, Germany (Gfroerer) Helios Clinic Berlin-Buch, Berlin, Germany (Bujotzek, Lariviere, Schumacher, Tiefenthaler) Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany (Beker) Mater Research Institute, University of Queensland, Brisbane, QLD, Australia (Beker, Collins) Neonatal Services, Mercy Hospital for Women, Melbourne, VIC, Australia (Collins) Joan Kirner Women's & Children's, Sunshine Hospital, Melbourne, VIC, Australia (Kamlin, Theda) Department of Newborn Research, Royal Women's Hospital, Melbourne, VIC, Australia (Kamlin, Theda) University of Melbourne, Melbourne, VIC, Australia (Kamlin, Theda) Murdoch Children's Research Institute, Melbourne, VIC, Australia (Konig) Medicum Wesemlin, Department of Paediatrics, Lucerne, Switzerland (Malhotra, Tan, Nold) Monash Newborn, Monash Children's Hospital, Melbourne, VIC, Australia (Veldman) Department of Pediatrics, Liebig University Hospital, Giessen, Germany (Ellisdon, Whisstock) Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia (Whisstock) Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, Australia | Issue Date: | 24-Dec-2020 | Copyright year: | 2020 | Publisher: | Nature Research | Place of publication: | United Kingdom | Publication information: | Nature Communications. 11 (1) (no pagination), 2020. Article Number: 5794. Date of Publication: December 2020. | Journal: | Nature Communications | 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-RORgammat+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORgammat+ 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.Copyright © 2020, The Author(s). | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1038/s41467-020-19400-w | PubMed URL: | 33188181 [http://www.ncbi.nlm.nih.gov/pubmed/?term=33188181] | ISSN: | 2041-1723 (electronic) | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/28976 | Type: | Article | Subjects: | toll like receptor 4/ec [Endogenous Compound] toll like receptor 5/ec [Endogenous Compound] toll like receptor 6/ec [Endogenous Compound] toll like receptor 7/ec [Endogenous Compound] toll like receptor 8/ec [Endogenous Compound] toll like receptor 9/ec [Endogenous Compound] transcription factor GATA 3/ec [Endogenous Compound] transcription factor T bet/ec [Endogenous Compound] transforming growth factor beta/ec [Endogenous Compound] toll like receptor 11/ec [Endogenous Compound] adult animal cell animal experiment animal model article controlled study human human tissue immunology infant *innate immunity intestine injury low birth weight lymphoid cell male microbial diversity monocyte mortality rate mouse *necrotizing enterocolitis/et [Etiology] newborn nonhuman pneumatosis intestinalis prematurity Th17 cell CXCL1 chemokine/ec [Endogenous Compound] interleukin 1 receptor/ec [Endogenous Compound] interleukin 10/ec [Endogenous Compound] interleukin 17/ec [Endogenous Compound] interleukin 17F/ec [Endogenous Compound] interleukin 18/ec [Endogenous Compound] interleukin 1beta/ec [Endogenous Compound] interleukin 21/ec [Endogenous Compound] interleukin 22/ec [Endogenous Compound] interleukin 23/ec [Endogenous Compound] interleukin 37/ec [Endogenous Compound] interleukin 4/ec [Endogenous Compound] interleukin 6/ec [Endogenous Compound] messenger RNA/ec [Endogenous Compound] natural cytotoxicity triggering receptor 1/ec [Endogenous Compound] retinoid related orphan receptor gamma/ec [Endogenous Compound] toll like receptor 1/ec [Endogenous Compound] toll like receptor 10/ec [Endogenous Compound] toll like receptor 2/ec [Endogenous Compound] toll like receptor 3/ec [Endogenous Compound] low birth weight lymphoid cell male microbial diversity monocyte mortality rate mouse *necrotizing enterocolitis / *etiology newborn nonhuman animal experiment prematurity Th17 cell animal cell adult pneumatosis intestinalis animal model Article controlled study human human tissue immunology infant *innate immunity intestine injury |
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