Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities.

Autor: Cho SX; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.; Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan., Rudloff I; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia., Lao JC; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia., Pang MA; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia., Goldberg R; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medicine, Monash University, Melbourne, VIC, Australia.; Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia., Bui CB; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia., McLean CA; Department of Anatomical Pathology, Alfred Hospital, Melbourne, VIC, Australia.; Central Clinical School, Monash University, Melbourne, VIC, Australia., Stock M; ZIK Septomics, Jena University Hospital, Jena, Germany., Klassert TE; ZIK Septomics, Jena University Hospital, Jena, Germany., Slevogt H; ZIK Septomics, Jena University Hospital, Jena, Germany., Mangan NE; Department of Molecular and Translational Science, Monash University, Melbourne, VIC, Australia.; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia., Cheng W; Department of Surgery, Beijing United Family Hospital, Beijing, China.; Capital Institute of Pediatrics, Beijing, China., Fischer D; Department of Pediatrics, Goethe University Hospital, Frankfurt, Germany.; Department of Pediatrics, St. Vincenz Hospital, Limburg, Germany., Gfroerer S; Department of Pediatric Surgery, Goethe University Hospital, Frankfurt, Germany.; Helios Clinic Berlin-Buch, Berlin, Germany., Sandhu MK; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.; Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia., Ngo D; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia., Bujotzek A; Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany., Lariviere L; Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany., Schumacher F; Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany., Tiefenthaler G; Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany., Beker F; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia.; Neonatal Services, Mercy Hospital for Women, Melbourne, VIC, Australia., Collins C; Neonatal Services, Mercy Hospital for Women, Melbourne, VIC, Australia.; Joan Kirner Women's & Children's, Sunshine Hospital, Melbourne, VIC, Australia., Kamlin COF; Department of Newborn Research, Royal Women's Hospital, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia.; Murdoch Children's Research Institute, Melbourne, VIC, Australia., König K; Medicum Wesemlin, Department of Paediatrics, Lucerne, Switzerland., Malhotra A; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.; Monash Newborn, Monash Children's Hospital, Melbourne, VIC, Australia., Tan K; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.; Monash Newborn, Monash Children's Hospital, Melbourne, VIC, Australia., Theda C; Department of Newborn Research, Royal Women's Hospital, Melbourne, VIC, Australia.; University of Melbourne, Melbourne, VIC, Australia.; Murdoch Children's Research Institute, Melbourne, VIC, Australia., Veldman A; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.; Department of Pediatrics, St. Vincenz Hospital, Limburg, Germany.; Department of Pediatrics, Liebig University Hospital, Giessen, Germany., Ellisdon AM; Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia., Whisstock JC; Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia.; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, Australia., Berger PJ; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia., Nold-Petry CA; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia., Nold MF; Department of Paediatrics, Monash University, Melbourne, VIC, Australia. marcel.nold@monash.edu.; Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia. marcel.nold@monash.edu.; Monash Newborn, Monash Children's Hospital, Melbourne, VIC, Australia. marcel.nold@monash.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Nov 13; Vol. 11 (1), pp. 5794. Date of Electronic Publication: 2020 Nov 13.
DOI: 10.1038/s41467-020-19400-w
Abstrakt: 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.
Databáze: MEDLINE