Single-Immunoglobulin Interleukin-1-Related Receptor regulates vulnerability to TLR4-mediated necrotizing enterocolitis in a mouse model

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.

Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities

“…The IL-37-induced baseline increase in IL-1R8 likely further augments this inherent protectiveness of the intestinal milieu in IL-37tg, given that loss-of-function mutations in IL1R8 (gene also called SIGIRR) are associated with NEC 74 , and that IL-1R8 is a negative regulator of IL-1R-and TLR-dependent inflammation 65,75 . Indeed, IL-1R8-deficiency leads to TLR4 hyper-responsiveness and more severe intestinal inflammation and tissue injury in NEC models 76 . The localization of IL-1R8 to IEC of neonatal mice 76 is consistent with our findings in human preterm neonates.…”

Porcine Circovirus Type 2 Induces Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR) Downregulation to Promote Interleukin-1β Upregulation in Porcine Alveolar Macrophage

“…SIGIRR has been suggested to function as a blocking receptor because of its interaction with key signaling molecules (MyD88, IRAK, and TRAF6) of the IL-1R/TLR-NF-κB signaling pathway [16,51]. IL-1β was upregulated significantly in SIGIRR-deficient mice with necrotizing enterocolitis [52]. SIGIRR may be a key regulator of inflammation, which in physiological conditions inhibits activation of IL-1R/TLR to avoid detrimental inflammation, while during inflammatory responses or in pathological conditions SIGIRR is downregulated thereby permitting IL-1R/TLR activation [14,18,53,54].…”

Toll-Like Receptor–Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis

“…One of the most important pathways that mediates the balance between injury and repair in the premature intestine, and that plays a key role in NEC pathogenesis, is the Toll-like receptor (TLR) family of bacterial recognition receptors, specifically Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharide (LPS) on gram-negative bacteria. 17 Key evidence linking TLR4 with the pathogenesis of NEC include the findings that the expression of TLR4 in the intestinal epithelium is increased in mice and human beings with NEC, 18 , 19 activating mutations in TLR4 signaling pathways are seen in human NEC, 20 , 21 , 22 , 23 and novel TLR4 inhibitors prevent and treat NEC in animal models and attenuate proinflammatory signaling in human NEC tissue ex vivo, 24 whereas mice lacking TLR4 in the intestinal epithelium are protected from NEC development. 25 It is noteworthy that there are other pathways that also play a role in the pathogenesis of NEC, many of which are downstream of TLR4, and these have been reviewed extensively by us recently elsewhere, 15 while other investigators have shown that the premature intestine is more prone to inflammation 26 in part through the expression of innate immune response genes including TLR4 and its gene family members, 27 which is supportive of this concept.…”