Aging-US: Lipopolysaccharide upregulates miR-132/212 in Hirschsprung-associated enterocolitis11-10-2020
Aging-US recently published "Lipopolysaccharide upregulates miR-132/212 in Hirschsprung-associated enterocolitis, facilitating pyroptosis by activating NLRP3 inflammasome via targeting Sirtuin 1 (SIRT1)" which reported that MiR-132 and miR-212 were up-regulated in HAEC dilated tissues and LPS-treated mice enteritis samples.
LPS-stimulated HT29 cells showed a high expression of miR-132 and miR-212. QRT-PCR analysis, western blotting, luciferase reporter assay, and flow cytometric analysis were carried out in vitro, showing that miR-132 and miR-212 could directly inhibit Sirtuin 1 expression.
Consequently, SIRT1 deficiency in LPS-stimulated HT29 cell line and LPS-treated mice activated NLRP3 inflammasome and Caspase-1-mediated pyroptosis.
In conclusion, LPS upregulated miR-132 and miR-212 expression in HAEC, suppressing SIRT1 and facilitating NLRP3 inflammasome activation, which induced pyroptosis.
The Aging-US authors illustrated the role of LPS/miR-132/-212/SIRT1/NLRP3 regulatory network in the occurrence and progression of HAEC and proposed a new molecular pathway for LPS-mediated cell pyroptosis.
Dr. Meiling Tong from The Nanjing Medical University as well as Dr. Weibing Tang from The Children’s Hospital of Nanjing Medical University said, "Hirschsprung disease (HSCR) is a neonatal neurocristopathy arising from a defect of enteric neurons in the distal colon, with an incidence of 1 in 5000 live births (live born infants)"
Despite the poor understanding of the pathophysiology of HAEC, several recent studies have shed light on the details of HAEC development.
Their previous study has also found that gram-negative bacteria-released LPS is prominently increased in postoperative HAEC patients, suggesting that gut microbiota dysbiosis and subsequently released LPS appeared to be important elements of HAEC.
Interestingly, LPS can mediate cell pyroptosis through a non-classical cell pyroptosis pathway, which plays an important role in intestinal inflammation.
Therefore, this study innovatively proposed a new molecular pathway in which LPS mediates pyroptosis indirectly, and aimed at defining the pathophysiological role of LPS/miR-132/-212/SIRT1 in HAEC.
Figure 6. Possible mechanism by which LPS upregulates miR-132/-212 in Hirschsprung-associated enterocolitis, facilitating pyroptosis by activating NLRP3 inflammasome via targeting Sirtuin 1 (SIRT1).
Herein, the authors reported that miR-132/-212 was markedly increased in patients with postoperative HAEC and experimental animal models and discovered the ability of LPS to promote miR-132/-212 expression.
The Tong/Tang Research Team concluded in their Aging-US Research Paper that they explored the role of LPS/miR-132/-212-SIRT1-NLRP3 regulatory network in HAEC by experiments in vitro carried out in LPS-injured HT29 cell line.
The data presented in this study showed that LPS-induced upregulation of miR-132/-212, triggered activation of NLRP3 inflammasome and succedent pyroptosis in patients with postoperative HAEC and LPS-stimulated HT29 cell line and LPS-treated mice.
Furthermore, miR-132/-212 inhibitor and SIRT1 overexpression transfection moderated LPS-induced cell pyroptosis .
However, the above effect was not enough for abrogating cell pyroptosis, supporting the notion that other types of cell injury mechanisms may also exist. Summarily, our study provides a mechanistic explanation of LPS/miR-132/-212/SIRT1/NLRP3-Caspase-1 inflammasome in the progression of HAEC: LPS induces upregulation of miR-132/-212, which triggers Caspase-1-dependent pyroptosis via inhibiting SIRT1. It also proposes a new molecular pathway for LPS-mediated cell pyroptosis, which provides new insights into understanding the molecular mechanism of cell pyroptosis.
Full Text - https://doi.org/10.18632/aging.103852
Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.