Let-7d-5p suppresses inflammatory response in neonatal rats with necrotizing enterocolitis via LGALS3-mediated TLR4/NF-κB signaling pathway

Abstract

Necrotizing enterocolitis (NEC) is an acute intestinal condition accounting for severe mortality and morbidity in preterm infants. This study aimed to identify the possible roles of let-7d-5p in neonatal rats with NEC. The differentially expressed genes (DEGs) related to NEC were initially screened in silico. After establishment of NEC rat models, the measurement of the expression of let-7d-5p, galectin-3 (LGALS3), toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) as well as proinflammatory cytokines (TNF-α, IL-1b and IL-6) was conducted. The interaction between let-7d-5p and LGALS3 or Argonaute2 (AGO2) was identified. Gain- and loss-function approaches were then performed in an attempt to investigate the regulatory roles of let-7d-5p and LGALS3 in inflammation and cell apoptosis in NEC neonatal rats. Let-7d-5p was poorly expressed, while LGALS3, TLR4 and NF-κB were highly expressed in the intestinal tissues of NEC rats. Over-expression of let-7d-5p resulted in decreased levels of proinflammatory factors in the intestinal tissues of NEC rats. Through sequential experimentation, let-7d-5p was identified to target LGALS3 and bind to AGO2. In addition, LGALS3 silencing or LPS treatment blocked the TLR4/NF-κB signaling pathway, thereby suppressing intestinal epithelial cell apoptosis and inflammation in NEC. Collectively, let-7d-5p might exercise its inhibitory properties in the inflammatory response and intestinal epithelial cell apoptosis in NEC neonatal rats via inactivation of the LGALS3-dependent TLR4/NF-κB signaling pathway.

Can altered colostrum miRNA expression profile after cesarean delivery be a risk factor for autoimmune diseases?

“…In the study conducted by Zhang et al 27 in an experimental Parkinson's animal model, it was reported that miR‐let‐7a suppresses microglia inflammation by targeting the STAT‐3 pathway. Sun et al 28 reported in their study on neonatal rats with necrotizing enterocolitis that miRNA‐let‐7d‐5p suppresses the inflammatory response via galectin‐3 (LGALS3)–mediated TLR4/NF‐B signaling. Marioto et al 29 investigated the expression profile of miRNAs associated with the immune response due to pulmonary infection at 28th and 56th days of infection in mice infected with Paracoccidioides brasiliensis.…”

Role of omega-3 polyunsaturated fatty acids, citrus pectin, and milk-derived exosomes on intestinal barrier integrity and immunity in animals

“…The mechanism by which Gal-3 regulates inflammatory response is multifaceted. In intestine, it stimulates pro-inflammatory responses by acting as ligands to TLRs of IECs [ 117 , 118 ] [Fig. 4 B].…”

“…4 B]. Previously, in rat pups, induction of experimental NEC was shown to activate Gal-3-mediated TLR4/NF-κB signaling [ 118 ]. Alternatively, Gal-3 act as PRRs to pathogens or LPS and recruit immune cells for opsonization [ 117 ] [Fig.…”

Roles of exosomes and exosome-derived miRNAs in pulmonary fibrosis

“…In recent years, the role of let-7d-5p in degenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis has been investigated, and it was significantly downregulated in both diseases ( Kumar et al, 2013 ; Mendes-Silva et al, 2016 ; Chen et al, 2018 ; Liguori et al, 2018 ). Moreover, let-7d-5p showed anti-inflammatory properties and inhibited intestinal epithelial cell apoptosis in necrotizing enterocolitis of neonatal rats by negatively regulating the LGALS3-dependent TLR4/NF-κB signaling pathway ( Sun et al, 2020 ). The expression of let-7d-5p was downregulated both in the skin of systemic sclerosis and in the lungs of PF ( Bagnato et al, 2017 ).…”