Abstract
Objective: Necrotizing enterocolitis (NEC) is a gastrointestinal emergency with a severe inflammation storm, intestinal necrosis, and perforation. MicroRNA-146a-5p (miR-146a-5p) has been reported to be a valuable anti-inflammatory factor in various intestinal inflammatory disorders. However, the role of miR-146a-5p in NEC, its effects on nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome, and its downstream inflammatory factors remain unknown. This study aimed to investigate the role of miR-146a-5p and NLRP3 inflammasome and its downstream inflammatory factors in NEC development.Methods: The expression levels of miR-146a and NLRP3 inflammasome were investigated in intestinal tissues. Next, the mechanism by which miR-146a-5p regulates NLRP3 inflammasome activation was explored in vitro in THP-1 cells. Finally, to identify the effects of miR-146a-5p on NEC in vivo, NEC mice were transinfected with miR-146a-5p overexpression adenovirus before the occurrence of NEC.Results: NLRP3 inflammasome enzymatic protein caspase-1 and its downstream inflammatory factors increased in NEC intestinal samples in both humans and mice, and miR-146a-5p expression level was increased and mainly expressed in the macrophages of the affected intestine. In vitro, only miR-146a-5p mimic inhibited NLRP3 inflammasome downstream inflammatory factors and its upstream protein chloride intracellular channel protein 4 (CLIC4) expression in cellular membrane in the THP-1 cell line, and this only occurred under mild/moderate LPS concentration. MiR-146a-5p overexpression adenovirus transfection reduced CLIC4 cellular membrane expression and inhibited NLRP3 downstream factors increasing in vivo. After the transfection of miR-146a-5p adenovirus, the survival rate of NEC mice was increased, and intestinal injury was ameliorated.Conclusion: MiR-146a-5p inhibited NLRP3 inflammasome downstream inflammatory factors and CLIC4 membrane expression in NEC. Additionally, miR-146a-5p could attenuate inflammation and intestinal injury in the NEC-affected intestine.
Highlights
Necrotizing enterocolitis (NEC) is one of the most serious and common digestive system emergencies in premature infants and is characterized by an inflammation storm as well as intestinal necrosis and perforation
nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome enzymatic protein caspase-1 and its downstream inflammatory factors increased in NEC intestinal samples in both humans and mice, and miR-146a-5p expression level was increased and mainly expressed in the macrophages of the affected intestine
MiR-146a-5p overexpression adenovirus transfection reduced chloride intracellular channel protein 4 (CLIC4) cellular membrane expression and inhibited NLRP3 downstream factors increasing in vivo
Summary
Necrotizing enterocolitis (NEC) is one of the most serious and common digestive system emergencies in premature infants and is characterized by an inflammation storm as well as intestinal necrosis and perforation. Macrophages are the first component of the innate immune response. MicroRNA-146a (miR-146a) is a valuable negative regulator of innate immune response that functions by controlling the lipopolysaccharide (LPS) Toll-like 4 receptor signaling pathway and targeting TRAF6 and IRAK1 (Tang et al, 2009; Chassin et al, 2010, 2012; Saba et al, 2014; Chen et al, 2018). MiR-146a plays a vital role in the macrophage-induced innate immune response (Jiang et al, 2012), and its dysregulation has been observed in autoimmune diseases (Nakasa et al, 2008; Tang et al, 2009). The role of miR-146a in NEC innate immunity is still unclear
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