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The Low-density Lipoprotein Receptor-related Protein 6 Pathway in the Treatment of Intestinal Barrier Dysfunction Induced by Hypoxia and Intestinal Microbiota through the Wnt/β-catenin Pathway.

ABSTRACT: Our study is to explore the key molecular of Low-density lipoprotein receptor-related protein 6 (LRP6) and the related Wnt/β-catenin pathway regulated by LRP6 during the intestinal barrier dysfunction. Colorectal protein profile analysis showed that LRP6 expression was decreased in dextran sulfate sodium (DSS)-induced colitis mice, and mice received fecal bacteria transplantation from stroke patients. Mice with intestinal hypoxia and intestinal epithelial cells cultured in hypoxia showed decreased expression of LRP6. Overexpression of LPR6 or its N-terminus rescued the Wnt/β-catenin signaling pathway which was inhibited by hypoxia and endoplasmic reticulum stress. In mice overexpressing of LRP6, the expression of β-catenin and DKK1 increased, Bcl2 decreased, and Bax increased. Mice with LRP6 knockout showed an opposite trend, and the expression of Claudin2, Occludin and ZO-1 decreased. Two drugs, curcumin and auranofin could alleviate intestinal barrier damage in DSS-induced colitis mice by targeting LRP-6. Therefore, gut microbiota dysbiosis and hypoxia can inhibit the LRP6 and Wnt/β-catenin pathway, and drugs targeting LRP6 can protect the intestinal barrier.

SUBMITTER: Liu Z

PROVIDER: S-EPMC9295061 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The Low-density Lipoprotein Receptor-related Protein 6 Pathway in the Treatment of Intestinal Barrier Dysfunction Induced by Hypoxia and Intestinal Microbiota through the Wnt/β-catenin Pathway.

Liu Zhihua Z Li Chao C Liu Min M Song Zhen Z Moyer Mary Pat MP Su Dan D

International journal of biological sciences 20220711 11

Our study is to explore the key molecular of Low-density lipoprotein receptor-related protein 6 (LRP6) and the related Wnt/β-catenin pathway regulated by LRP6 during the intestinal barrier dysfunction. Colorectal protein profile analysis showed that LRP6 expression was decreased in dextran sulfate sodium (DSS)-induced colitis mice, and mice received fecal bacteria transplantation from stroke patients. Mice with intestinal hypoxia and intestinal epithelial cells cultured in hypoxia showed decreas ...[more]

PMID: 35864969

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Project description:BackgroundDisruption of the blood-brain barrier (BBB) after a stroke can lead to brain injury and neurological impairment. Previous work confirmed the involvement of the immunoproteasome subunit of low molecular mass peptide 2 (LMP2) in the pathophysiology of ischemia stroke. However, the relationship between the immunoproteasome LMP2 and the BBB remains unclear.MethodsAdult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion/reperfusion (MCAO/R). Three days before MCAO, the rats were treated with lentivirus-mediated LMP2 shRNA preparations by stereotactical injection into the ipsilateral hemispheric region. The rat brain microvascular endothelial cell (RBMVEC) line was exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic ischemic conditions in vitro. The RNA interference-mediated knockdown of LMP2 or β-catenin was analysed in vivo and in vitro. Analysis of the quantity of extravasated Evans blue (EB) and cerebral fluorescent angiography were performed to evaluate the integrity of the BBB. Immunofluorescence and Western blotting were employed to detect the expression of target proteins. Cell migration was evaluated using a scratch migration assay. The results of immunofluorescence, Western blotting and cell migration were quantified using the software ImageJ (Version 1.53m). Parametric data from different groups were compared using one-way ANOVA followed by the least significant difference (LSD) test.ResultsCerebral ischemia led to lower levels of structural components of the BBB such as tight junction proteins (occludin, claudin-1 and ZO-1) in the MCAO/R group compared with the sham group (P < 0.001). However, inhibition of the immunoproteasome LMP2 restored the expression of these proteins, resulting in higher levels of occludin, claudin-1 and ZO-1 in the LMP2-shRNA group compared with the control-shRNA group (P < 0.001). In addition, inhibition of the immunoproteasome LMP2 contributed to higher microvascular density and decreased BBB permeability [e.g., the quantity of extravasated EB: LMP2-shRNA group (58.54 ± 7.37) µg/g vs. control-shRNA group (103.74 ± 4.32) µg/g, P < 0.001], and promoted the upregulation of Wnt-3a and β-catenin proteins in rats following MCAO/R. In vitro experiments, OGD/R induced marked upregulation of LMP2, proapoptotic protein Bax and cleaved caspase-3, and downregulation of occludin, claudin-1, ZO-1 and Bcl-2, as well as inhibition of the Wnt/β-catenin pathway Wnt-3a and β-catenin proteins in RBMVECs, compared with the control group under normal culture conditions (P < 0.001). However, silencing of LMP2 gene expression reversed these protein changes and promoted proliferation and migration of RBMVECs following OGD/R. Silencing of β-catenin by transfection of RBMVECs with β-catenin-siRNA aggravated the downregulation of tight junction proteins, and reduced the proliferation and migration of RBMVECs following OGD/R, compared with the control-siRNA group (P < 0.001). LMP2-siRNA and β-catenin-siRNA co-transfection partly counteracted the beneficial effects of silencing LMP2-siRNA on the levels of tight junction proteins in RBMVECs exposed to OGD/R.ConclusionThis study suggests that inhibition of the immunoproteasome LMP2 ameliorates ischemia/hypoxia-induced BBB injury, and that the molecular mechanism involves the immunoproteasome-regulated activation of the Wnt/β-catenin signalling pathway under ischemic conditions.

Project description:IntroductionThe intestinal mucosal barrier is an important line of defense for the body, protecting it from intestinal bacteria, endotoxins, and antigens. Cisplatin, a clinical important chemotherapy medicine, is found the side effect with impairing intestinal epithelial cells' structure and function, even causes intestinal mucositis which causes patients immense suffering and hinders the process of cancer treatment. Chlorogenic acid, as the component only second to caffeine in coffee, has been proved the contribution on cardiovascular and gastrointestinal benefits. So, we investigate the protective effect of chlorogenic acid on cisplatin induced intestinal barrier structure and function injury in mice from the perspective of gut microbiota.MethodsC57BL/6J mice were divided into 4 groups, including the control group, a cisplatin group, a chlorogenic acid treatment group receiving intraperitoneal injections alongside cisplatin (Cis + CGA1), and the last group pre-treated with chlorogenic acid before cisplatin administration (Cis + CGA2). The inflammation factor of IL-6, IL-1β, and TNF-α in colonic tissue and serum were detected, respectively. To explore the protection of chlorogenic acid on mucosal barrier's integrity, we also detected the fecal LPS and the expression of occludin and ZO-1 proteins in colon tissue. And H&E staining was used to study the histopathological conditions of the colon tissue. Moreover, this article also utilized16S rDNA sequencing to analyze the gut microbiota of feces.ResultsChlorogenic acid administration reduced IL-6, IL-1β, and TNF-α level in both colon tissue and serum compared to the cisplatin alone treatment group. Furthermore, chlorogenic acid pretreatment notably improved intestinal barrier integrity by enhancing the expression of occludin and ZO-1 proteins in colon tissues. Moreover, 16S rDNA sequencing showed that compared with the control group, cisplatin group showed a reduced microbiota diversity, elevating abundance of Proteobacteria and pro-inflammatory environment of the increased Firmicutes/Bacteroidetes (F/B) ratio. However, chlorogenic acid treatment especially the pretreatment reversed the reduced microbiota diversity, elevating abundance of Proteobacteria and F/B ratio.DiscussionMicrobiota diversity and all results suggest that chlorogenic acid treatment was able to mitigate these intestinal microbiota disorder and diversity reduction induced by cisplatin, effectively offer a protective effect against the inflammatory response and destruction of the mucosal barrier in the intestines caused by cisplatin.

Dataset Information

The Low-density Lipoprotein Receptor-related Protein 6 Pathway in the Treatment of Intestinal Barrier Dysfunction Induced by Hypoxia and Intestinal Microbiota through the Wnt/β-catenin Pathway.

Publications

The Low-density Lipoprotein Receptor-related Protein 6 Pathway in the Treatment of Intestinal Barrier Dysfunction Induced by Hypoxia and Intestinal Microbiota through the Wnt/β-catenin Pathway.

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