Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities
Steven Cho, Ina Rudloff, Jason Chun Lao, Merrin A. Pang, Rimma Goldberg, Christine B. Bui, Catriona McLean, Magdalena Stock, Tilman E. Klassert, Hortense Slevogt, Niamh E. Mangan, Wei Cheng, Doris Fischer, Stefan Gfroerer, Manjeet Sandhu, Devi Ngo, Alexander Bujotzek, Laurent Larivière, Felix Schumacher, Georg Tiefenthaler, Friederike Beker, Clare L. Collins, C. Omar F. Kamlin, Kai König, Anil K. Malhotra, Kenneth Tan, Christiane Theda, Alex Veldman, Andrew M. Ellisdon, James C. Whisstock, Philip J. Berger, Claudia A. Nold‐Petry, Marcel F. Nold
Abstract
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/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.