A Promising Genetic Target for a Deadly Disease: Single Immunoglobulin Interleukin 1 (SIGIRR) Mutations in Necrotizing Enterocolitis (2021)

Necrotizing enterocolitis (NEC) is a deadly disease that primarily affects premature infants, but the precise etiology is not well understood. Premature infants are predisposed to NEC because of their immature intestinal epithelium and host defenses, as well as bacterial dysbiosis that precedes disease onset. Data from mouse models suggest that NEC arises from activation of the innate immune receptor, Toll-like receptor 4 (TLR4), by its ligand lipopolysaccharide derived from gram-negative bacteria in abundance after dysbiosis occurs. Several recent lines of investigation into the underlying causes of NEC have focused on identifying genetic predispositions to the disease. A promising genetic target includes a negative regulator of TLR4 signaling, called single immunoglobulin interleukin 1 (SIGIRR), mutations of which have been identified previously in infants with NEC.1Sampath V. Menden H. Helbling D. Li K. Gastonguay A. Ramchandran R. Dimmock D.P. SIGIRR genetic variants in premature infants with necrotizing enterocolitis.Pediatrics. 2015; 135: e1530-e1534Crossref PubMed Scopus (47) Google Scholar How mutations in SIGIRR affect the development of NEC has remained undefined. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Yu et al2Yu W. Haque I. Venkatraman A. et al.SIGIRR mutation identified in human necrotizing enterocolitis (NEC) disrupts STAT3-dependent microRNA expression in neonatal gut.Cell Mol Gastroenterol Hepatol. 2022; 13: 425-440Abstract Full Text Full Text PDF Scopus (5) Google Scholar explore how SIGIRR mutations contribute to NEC pathogenesis and induce TLR hyper-responsiveness in the postnatal intestine. Toward this end, Yu et al2Yu W. Haque I. Venkatraman A. et al.SIGIRR mutation identified in human necrotizing enterocolitis (NEC) disrupts STAT3-dependent microRNA expression in neonatal gut.Cell Mol Gastroenterol Hepatol. 2022; 13: 425-440Abstract Full Text Full Text PDF Scopus (5) Google Scholar generated a transgenic mouse line with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) encoding a novel SIGIRR mutation (p. Y168X) that was discovered in an infant who died from a severe form of NEC.1Sampath V. Menden H. Helbling D. Li K. Gastonguay A. Ramchandran R. Dimmock D.P. SIGIRR genetic variants in premature infants with necrotizing enterocolitis.Pediatrics. 2015; 135: e1530-e1534Crossref PubMed Scopus (47) Google Scholar Interestingly, the SIGIRRTg mice showed exaggerated inflammation within the intestine along with nuclear factor-κB activation, a hallmark of TLR4 signaling. In further mechanistic studies, using RNA interference, SIGIRR was knocked down in human intestinal epithelial cells, which led to the decreased expression of small noncoding RNAs called microRNAs, specifically, microRNA146a and microRNA155, which have been shown previously to be anti-inflammatory. In seeking to determine the signaling pathways mediating this effect, Yu et al2Yu W. Haque I. Venkatraman A. et al.SIGIRR mutation identified in human necrotizing enterocolitis (NEC) disrupts STAT3-dependent microRNA expression in neonatal gut.Cell Mol Gastroenterol Hepatol. 2022; 13: 425-440Abstract Full Text Full Text PDF Scopus (5) Google Scholar further showed that the phosphorylation of signal transducer and activator of transcription 3 (STAT3) was reduced in the SIGIRR-knockdown human intestinal epithelial cells. Yu et al2Yu W. Haque I. Venkatraman A. et al.SIGIRR mutation identified in human necrotizing enterocolitis (NEC) disrupts STAT3-dependent microRNA expression in neonatal gut.Cell Mol Gastroenterol Hepatol. 2022; 13: 425-440Abstract Full Text Full Text PDF Scopus (5) Google Scholar also showed that STAT3 could bind directly to the promoters of the microRNAs and activate expression in a manner dependent on SIGIRR. These results suggest that SIGIRR can regulate the expression of microRNAs in intestinal epithelial cells in association with the phosphorylation of STAT3, uncovering a novel signaling pathway involved in the neonatal intestine. Through immunoprecipitation, SIGIRR overexpression, and the use of an interleukin Receptor Associated Kinase (IRAK) inhibitor, they were able to conclude that regulation of STAT3 phosphorylation is mediated through its interaction with IRAK1. Furthermore, expression levels of microRNAs decreased with IRAK1 inhibition in a dose-dependent manner. Yu et al2Yu W. Haque I. Venkatraman A. et al.SIGIRR mutation identified in human necrotizing enterocolitis (NEC) disrupts STAT3-dependent microRNA expression in neonatal gut.Cell Mol Gastroenterol Hepatol. 2022; 13: 425-440Abstract Full Text Full Text PDF Scopus (5) Google Scholar showed in human intestinal epithelial cells that SIGIRR inhibition of the proinflammatory response induced by the TLR5 ligand flagellin is dependent on STAT3-microRNA activation. They also showed that, in vivo, SIGGIRTg mice showed a spontaneous level of intestinal inflammation together with decreased intestinal microRNA expression, decreased STAT3 phosphorylation, and increased IRAK1 compared with wild-type littermates. Taken together, these data suggest that in the neonatal intestine the SIGIRR–IRAK1–STAT3 pathway can regulate microRNA expression, impacting intestinal inflammation. The findings presented by Yu et al2Yu W. Haque I. Venkatraman A. et al.SIGIRR mutation identified in human necrotizing enterocolitis (NEC) disrupts STAT3-dependent microRNA expression in neonatal gut.Cell Mol Gastroenterol Hepatol. 2022; 13: 425-440Abstract Full Text Full Text PDF Scopus (5) Google Scholar detail the mechanistic pathway of SIGIRR, an important negative regulator of TLR4, and how mutations can lead to exaggerated intestinal inflammation. Interestingly, this research team and others, also showed other contributing factors that impact the expression levels of SIGIRR in the preterm infant including the microbiome.3Cuna A. Yu W. Menden H.L. Feng L. Srinivasan P. Chavez-Bueno S. Ahmed I. Umar S. Sampath V. NEC-like intestinal injury is ameliorated by Lactobacillus rhamnosus GG in parallel with SIGIRR and A20 induction in neonatal mice.Pediatr Res. 2020; 88: 546-555Crossref PubMed Scopus (7) Google Scholar,4Wu W. Wang Y. Zou J. Long F. Yan H. Zeng L. Chen Y. Bifidobacterium adolescentis protects against necrotizing enterocolitis and upregulates TOLLIP and SIGIRR in premature neonatal rats.BMC Pediatr. 2017; 17: 1Crossref PubMed Scopus (22) Google Scholar Collectively, not only have these data shed light on the potential for genetic predisposition to NEC in the premature infant population, but also how multiple factors independently may disrupt the same regulatory pathways that lead to disease. The latter emphasizing the need for multiple concurrent therapeutic strategies to mitigate the development of this complex multifactorial disease. Studies focusing on identifying additional mutations can further delineate the various altered pathways in NEC pathogenesis and serve as a basis to determine how other modifiable factors, such as nutrition and the environment, can impact these pathways. Successful determination of modifiable factors will lead to practice change at the bedside and identification of therapeutic targets for future clinical trials to ultimately curtail this devastating disease. SIGIRR Mutation in Human Necrotizing Enterocolitis (NEC) Disrupts STAT3-Dependent microRNA Expression in Neonatal GutCellular and Molecular Gastroenterology and HepatologyVol. 13Issue 2PreviewSingle immunoglobulin interleukin-1–related receptor (SIGIRR) is a major inhibitor of Toll-like receptor signaling. Our laboratory identified a novel SIGIRR stop mutation (p.Y168X) in an infant who died of severe necrotizing enterocolitis (NEC). Herein, we investigated the mechanisms by which SIGIRR mutations induce Toll-like receptor hyper-responsiveness in the neonatal gut, disrupting postnatal intestinal adaptation. Full-Text PDF Open Access