RT Journal Article
SR Electronic
T1 Neonatal Injury Increases Gut Permeability by Epigenetically Suppressing E-Cadherin in Adulthood
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP ji1900639
DO 10.4049/jimmunol.1900639
A1 Kline, Kevin T.
A1 Lian, Haifeng
A1 Zhong, Xiaoying S.
A1 Luo, Xiuju
A1 Winston, John H.
A1 Cong, Yingzi
A1 Savidge, Tor C.
A1 Dashwood, Roderick H.
A1 Powell, Don W.
A1 Li, Qingjie
YR 2019
UL http://www.jimmunol.org/content/early/2019/12/27/jimmunol.1900639.abstract
AB NI in the colon affects barrier function later in life.NI sensitizes the Mir155 promoter for aberrant epigenetic activation.miR-155 suppresses E-cadherin protein expression in the colonic epithelium.Altered intestinal epithelial integrity is an important susceptibility trait in inflammatory bowel disease (IBD), and early life stressors are reported to contribute to this disease susceptibility in adulthood. To identify disease mechanisms associated with early-life trauma that exacerbate IBD in adulthood, we used a “double-hit” neonatal inflammation (NI) and adult inflammation (AI) model that exhibits more severe mucosal injury in the colon later in life. In this study, we explore the underlying mechanisms of this aggravated injury. In rats exposed to both NI and AI, we found sustained increases in colonic permeability accompanied by significantly attenuated expression of the epithelial junction protein E-cadherin. Quantitative RT-PCR revealed a decreased Cdh1 (gene of E-cadherin) mRNA expression in NI + AI rats compared with NI or AI rats. Next, we performed microRNA microarrays to identify potential regulators of E-cadherin in NI + AI rats. We confirmed the overexpression of miR-155, a predicted regulator of E-cadherin, and selected it for further analysis based on reported significance in human IBD. Using ingenuity pathway analysis software, the targets and related canonical pathway of miR-155 were analyzed. Mechanistic studies identified histone hyperacetylation at the Mir155 promoter in NI + AI rats, concomitant with elevated RNA polymerase II binding. In vitro, E-cadherin knockdown markedly increased epithelial cell permeability, as did overexpression of miR-155 mimics, which significantly suppressed E-cadherin protein. In vivo, NI + AI colonic permeability was significantly reversed with administration of miR-155 inhibitor rectally. Our collective findings indicate that early-life inflammatory stressors trigger a significant and sustained epithelial injury by suppressing E-cadherin through epigenetic mechanisms.