Journal article

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 Tiefenthaler Show all

Nature Communications | NATURE RESEARCH | Published : 2020

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 on..

View full abstract

Grants

Awarded by National Health and Medical Research Council


Awarded by ANZ Trustees Medical Research & Technology in Victoria Program


Awarded by Marian & E.H. Flack Trust


Awarded by National Heart Foundation of Australia


Awarded by German Research Foundation (DFG) through the TRR 124 FungiNet [Project A5]


Funding Acknowledgements

We thank Nikeh Shariatian, Jingyuan Shi, and Avisa Masarati for excellent technical assistance. A special thanks to Masako Yajima for invaluable advice regarding feeding nipple usage. This work was supported by the National Health and Medical Research Council Investigator Grant Leadership 1 [Grant 1173584] to C.A.N.-P., [Grant 1138926] to C.A.N.-P., M.F.N. and C.T., [Grant 1043845] and [Grant 1140820] to M.F.N. and C.A.N.-P., the ANZ Trustees Medical Research & Technology in Victoria Program [CT 20681] to C.A.N.-P., the Marian & E.H. Flack Trust [08/12] to C.A.N.-P. and M.F.N., the Fielding Foundation Innovation Award 2015 to M.F.N., a Future Leader Fellowship from the National Heart Foundation of Australia [CF14/3517] to C.A.N.-P., Fielding Foundation Fellowship 2019 to C.A.N.-P. by Monash University's Larkins Fellowship and the Hudson Institute's Star Recruitment Fellowship to M.F.N and Fielding Foundation Fellowship 2017 to M.F.N., a Monash University Faculty Postgraduate Research Scholarship to S.X.C. and J.C.L., Australian Government Research Training Program Scholarships to J.C.L. and C.B.B., by the German Research Foundation (DFG) through the TRR 124 FungiNet [project number 210879364, Project A5] to H.S., as well as the Operational Infrastructure Support Program of the Victorian Government. We also thank Sabine Schuster, Dominik Marks, Nadine Fiedler, and Christian Schantz for the supply of materials. The work on the second cohort of preterm infants was supported by a generous grant by CSL Ltd. We acknowledge the use of the facilities and technical assistance of Monash Histology Platform, Department of Anatomy and Developmental Biology, Monash University and FlowCore of Monash University.