Necrotizing Enterocolitis: LPS/TLR4-Induced Crosstalk Between Canonical TGF-β/Wnt/β-Catenin Pathways and PPARγ

Necrotizing enterocolitis (NEC) represents one of the major causes of morbidity and mortality in premature infants. Several recent studies, however, have contributed to a better understanding of the pathophysiology of this dreadful disease. Numerous intracellular pathways play a key role in NEC, namely: bacterial lipopolysaccharide (LPS), LPS toll-like receptor 4 (TLR4), canonical Wnt/β-catenin signaling and PPARγ. In a large number of pathologies, canonical Wnt/β-catenin signaling and PPARγ operate in opposition to one another, so that when one of the two pathways is overexpressed the other is downregulated and vice-versa. In NEC, activation of TLR4 by LPS leads to downregulation of the canonical Wnt/β-catenin signaling and upregulation of PPARγ. This review aims to shed light on the complex intracellular mechanisms involved in this pathophysiological profile by examining additional pathways such as the GSK-3β, NF-κB, TGF-β/Smads, and PI3K-Akt pathways.

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Recently Discovered Oligosaccharide Inhibits Toll-Like Receptor 4 and Prevents Intestinal Stem Cell Apoptosis in Experimental Necrotizing Enterocolitis

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2016.06.168 ◽

2016 ◽

Vol 223 (4) ◽

pp. S86

Author(s):

Laura Y. Martin ◽

Chhinder P. Sodhi ◽

Hongpeng Jia ◽

Yukihiro Yamaguchi ◽

Misty Good ◽

...

Keyword(s):

Stem Cell ◽

Necrotizing Enterocolitis ◽

Cell Apoptosis ◽

Intestinal Stem Cell ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Insights image for “The human milk oligosaccharides 2’-fucosyllactose and 6’-sialyllactose protect against the development of necrotizing enterocolitis by inhibiting toll-like receptor 4 signaling.”

Pediatric Research ◽

10.1038/s41390-020-01184-w ◽

2020 ◽

Author(s):

Chhinder P. Sodhi ◽

Peter Wipf ◽

Yukihiro Yamaguchi ◽

William B. Fulton ◽

Mark Kovler ◽

...

Keyword(s):

Human Milk ◽

Necrotizing Enterocolitis ◽

Toll Like Receptor ◽

Human Milk Oligosaccharides ◽

Toll Like Receptor 4 ◽

Milk Oligosaccharides

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Toll-Like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells

Hepatology ◽

10.1053/jhep.2003.50182 ◽

2003 ◽

Vol 37 (5) ◽

pp. 1043-1055 ◽

Cited By ~ 441

Author(s):

Y Paik

Keyword(s):

Hepatic Stellate Cells ◽

Stellate Cells ◽

Bacterial Lipopolysaccharide ◽

Toll Like Receptor ◽

Inflammatory Signaling ◽

Toll Like Receptor 4

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Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-γ: a molecular basis for priming and synergism with bacterial lipopolysaccharide

Blood ◽

10.1182/blood.v99.9.3427 ◽

2002 ◽

Vol 99 (9) ◽

pp. 3427-3431 ◽

Cited By ~ 200

Author(s):

Daniela Bosisio ◽

Nadia Polentarutti ◽

Marina Sironi ◽

Sergio Bernasconi ◽

Kensuke Miyake ◽

...

Keyword(s):

Surface Expression ◽

Interferon Γ ◽

Mononuclear Phagocytes ◽

Bacterial Lipopolysaccharide ◽

Interleukin 12 ◽

Mrna Levels ◽

Adapter Protein ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Tlr4 Mrna

Abstract In human monocytes and macrophages, interferon-γ (IFNγ) augmented mRNA and surface expression of toll-like receptor 4 (TLR4), a crucial component of the signaling receptor complex for bacterial lipopolysaccharide (LPS). Expression of the accessory component MD-2 and of the adapter protein MyD88 was also increased. LPS increased TLR4 mRNA levels, but concomitantly decreased its surface expression. IFNγ counteracted the LPS-induced downregulation of TLR4. IFNγ-primed monocytes showed increased responsiveness to LPS in terms of phosphorylation of the interleukin-1 receptor–associated kinase (IRAK; immediately downstream of the MyD88 adapter protein), NF-kB DNA binding activity, and, accordingly, of cytokine (tumor necrosis factor α [TNFα] and interleukin-12 [IL-12]) production. These results suggest that enhanced TLR4 expression underlies the long-known priming by IFNγ of mononuclear phagocytes for pathogen recognition and killing as well as its synergism with LPS in macrophage activation.

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