Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1α–miR-210 Signaling

Abstract

Neurotensin (NT) via its receptor 1 (NTR1) modulates development of colitis, decreases HIF-1α/PHD2 interaction, stabilizes and increases HIF-1α transcriptional activity and promotes intestinal angiogenesis. HIF-1α induces miR-210 expression while miR-210 is strongly up-regulated in response to NT in NCM460 human colonic epithelial cells overexpressing NTR1 (NCM460-NTR1). Here we examined whether NT activates a NTR1-HIF-1α-miR-210 cascade using in vitro (NCM460-NTR1 cells) and in vivo [transgenic mice overexpressing (HIF-1α-OE) or lacking HIF-1α (HIF-1α-KO) in intestinal epithelial cells and mice lacking NTR1 (NTR1-KO)] models. Pre-treatment of NCM460-NTR1 cells with the HIF-1α inhibitor PX-478 or silencing of HIF-1α (si-HIF-1α) attenuated miR-210 expression in response to NT. Intracolonic 2,4,6-trinitrobenzenesulfonic acid (TNBS) administration (2-day model) increased colonic miR-210 expression that was significantly reduced in NTR1-KO, HIF-1α-KO mice, and in wild-type (WT) mice pre-treated intracolonicaly with locked nucleic acid anti-miR-210 (LNA-anti-miR-210). In contrast, HIF-1α-OE mice showed increased miR-210 expression at baseline that was further increased following TNBS administration. HIF-1α-OE mice had also exacerbated TNBS-induced neovascularization compared to TNBS-exposed WT mice. TNBS-induced neovascularization was attenuated in HIF-1α-KO mice, or mice pre-treated intracolonicaly with anti-miR-210. Intracolonic anti-miR-210 also reduced colitis in response to TNBS (2 days). Importantly, miR-210 expression was increased in tissue samples from ulcerative colitis patients (UC). We conclude that NT exerts its proinflammatory and proangiogenic effects during acute colitis via an NTR1-PHD2/HIF-1α-miR-210 signaling pathway. Our results also demonstrate that miR-210 plays a proinflammatory role in the development of colitis.

MiRNA-210 induces microglial activation and regulates microglia-mediated neuroinflammation in neonatal hypoxic-ischemic encephalopathy

“…However, HIF-1α-miR-210 signaling has also been shown to play a proinflammatory role in intestinal epithelial cells during the development of acute colitis. 42 In psoriasis, HIF-1α was not a downstream target of miR-210 in CD4 + T cells of psoriasis, and upregulated miR-210 in psoriatic skins and CD4 + T cells promoted Th17 differentiation by targeting both STAT6 and LYN. 43 Consistently, upregulated miR-210 inhibited FOXP3 expression in CD4 + T cells of psoriasis vulgaris patients, which led to a defect in the immunosuppressive effects of Treg cells.…”

Coiled-coil domain containing 109B is a HIF1α-regulated gene critical for progression of human gliomas

“…5 e). U87MG and U251 cells were treated with siRNAs targeting HIF1α (si-HIF1α and si-HIF1α-2) or an inhibitor of HIF1α (PX478) [ 23 – 25 ] to test whether HIF1α is involved in regulating CCDC109B expression. Down-regulation of HIF1α reduced mRNA levels of CCDC109B (Additional file 2 : Figure S1A, B) and led to moderate decreases in CCDC109B protein (Fig.…”

The emerging role of lncRNAs in inflammatory bowel disease

“…A 13 amino acid length neuropeptide, neurotensin (NT), together with its high affinity G protein-coupled receptor 1 (NTR1), are believed to promote the development of UC and are expressed in the colon where they are upregulated in animal colitis models and UC patients 51 – 54 . NT/NTR1 signaling is involved in various colonic responses, including proinflammatory responses, and regulates several miRNAs associated with intestinal inflammation 55 , 56 .…”