Faculty Collaboration Database

Single-Immunoglobulin Interleukin-1-Related Receptor regulates vulnerability to TLR4-mediated necrotizing enterocolitis in a mouse model. Pediatr Res 2018 Jan;83(1-1):164-174

Date

08/29/2017

Pubmed ID

28846670

DOI

10.1038/pr.2017.211

Scopus ID

2-s2.0-85042040164 (requires institutional sign-in at Scopus site)   27 Citations

Abstract

BackgroundThe mechanisms underlying aberrant activation of intestinal Toll-like receptor 4 (TLR4) signaling in necrotizing enterocolitis (NEC) remain unclear. In this study, we examined the role of single-immunoglobulin interleukin-1 receptor-related molecule (SIGIRR), an inhibitor of TLR signaling, in modulating experimental NEC vulnerability in mice.MethodsExperimental NEC was induced in neonatal wild-type and SIGIRR-/- mice using hypoxia, formula-feeding, and lipopolysaccharide administration. Intestinal TLR canonical signaling, inflammation, apoptosis, and severity of experimental NEC were examined at baseline and after NEC induction in mice.ResultsSIGIRR is developmentally regulated in the neonatal intestine with a restricted expression after birth and a gradual increase by day 8. At baseline, breast-fed SIGIRR-/- mouse pups exhibited low-grade inflammation and TLR pathway activation compared with SIGIRR+/+ pups. With experimental NEC, SIGIRR-/- mice had significantly more intestinal interleukin (IL)-1β, KC (mouse homolog to IL-8), intercellular adhesion molecule-1 (ICAM-1), and interferon-beta (IFN-β) expression in association with the amplified TLR pathway activation. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, cleaved caspase 3, and severity of intestinal injury with NEC were worse in SIGIRR-/- mice in comparison with SIGIRR+/+ mice.ConclusionSIGIRR is a negative regulator of TLR4 signaling in the developing intestine, and its insufficiency results in native intestinal TLR hyper-responsiveness conducive to the development of severe experimental NEC in mice.

Author List

Fawley J, Cuna A, Menden HL, McElroy S, Umar S, Welak SR, Gourlay DM, Li X, Sampath V

Authors

David M. Gourlay MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Scott R. Welak MD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Apoptosis
Cytokines
Disease Models, Animal
Enterocolitis, Necrotizing
Hypoxia
Immunity, Innate
Inflammation
Lipopolysaccharides
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Phosphorylation
Receptors, Interleukin-1
Signal Transduction
Toll-Like Receptor 4