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

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 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. Necrotizing Enterocolitis (NEC) is an untreatable intestinal disease in infants. Here the authors show that human and experimental mouse NEC is associated with altered toll-like receptor expression in the intestine, enhanced Th17/type 3 polarization in adaptive immune and innate lymphoid cells, dysregulated microbiota, and reduced interleukin-37 signaling.

ENTEROCOLITIS; INNATE lymphoid cells; INTERLEUKIN-37; INTESTINAL diseases; PREMATURE infants

Nature Communications, 2020, Vol 11, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-020-19400-w