MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis in Mice

Yuhua Tian, Jiuzhi Xu, Yuan Li, Ran Zhao, Sujuan Du, Cong Lv, Wei Wu, Ruiqi Liu, Xiaole Sheng, Yongli Song, Xueyun Bi, Guilin Li, Mengzhen Li, Xi Wu, Pengbo Lou, Huiwen You, Wei Cui, Jinyue Sun, Jianwei Shuai, Fazheng Ren & 11 others Bing Zhang, Mingzhou Guo, Xiaohua Hou, Kaichun Wu, Lixiang Xue, Hongquan Zhang, Maksim V. Plikus, Yingzi Cong, Christopher J. Lengner, Zhanju Liu, Zhengquan Yu

    Research output: Contribution to journalArticle

    2 Citations (Scopus)

    Abstract

    Background & Aims: Levels of microRNA 31 (MIR31) are increased in intestinal tissues from patients with inflammatory bowel diseases and colitis-associated neoplasias. We investigated the effects of this microRNA on intestinal inflammation by studying mice with colitis. Methods: We obtained colon biopsy samples from 82 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 34 healthy individuals (controls) at Shanghai Tenth People's Hospital. MIR31- knockout mice and mice with conditional disruption of Mir31 specifically in the intestinal epithelium (MIR31 conditional knockouts) were given dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. We performed chromatin immunoprecipitation and luciferase assays to study proteins that regulate expression of MIR31, including STAT3 and p65, in LOVO colorectal cancer cells and organoids derived from mouse colon cells. Partially hydrolyzed alpha-lactalbumin was used to generate peptosome nanoparticles, and MIR31 mimics were loaded onto their surface using electrostatic adsorption. Peptosome–MIR31 mimic particles were encapsulated into oxidized konjac glucomannan (OKGM) microspheres, which were administered by enema into the large intestines of mice with DSS-induced colitis. Intestinal tissues were collected and analyzed by histology and immunohistochemistry. Results: Levels of MIR31 were increased in inflamed mucosa from patients with CD or UC, and from mice with colitis, compared with controls. STAT3 and nuclear factor-κB activated transcription of MIR31 in colorectal cancer cells and organoids in response to tumor necrosis factor and interleukin (IL)6. MIR31-knockout and conditional-knockout mice developed more severe colitis in response to DSS and TNBS, with increased immune responses, compared with control mice. MIR31 bound to 3ʹ untranslated regions of Il17ra and Il7r messenger RNAs (RNAs) (which encode receptors for the inflammatory cytokines IL17 and IL7) and Il6st mRNA (which encodes GP130, a cytokine signaling protein). These mRNAs and proteins were greater in MIR31-knockout mice with colitis, compared with control mice; MIR31 and MIR31 mimics inhibited their expression. MIR31 also promoted epithelial regeneration by regulating the WNT and Hippo signaling pathways. OKGM peptosome–MIR31 mimic microspheres localized to colonic epithelial cells in mice with colitis; they reduced the inflammatory response, increased body weight and colon length, and promoted epithelial cell proliferation. Conclusions: MIR31, increased in colon tissues from patients with CD or UC, reduces the inflammatory response in colon epithelium of mice by preventing expression of inflammatory cytokine receptors (Il7R and Il17RA) and signaling proteins (GP130). MIR31 also regulates the WNT and Hippo signaling pathways to promote epithelial regeneration following injury. OKGM peptosome–MIR31 microspheres localize to the colon epithelium of mice to reduce features of colitis. Transcript Profiling: GSE123556

    Original languageEnglish (US)
    Pages (from-to)2281-2296.e6
    JournalGastroenterology
    Volume156
    Issue number8
    DOIs
    StatePublished - Jun 1 2019

    Fingerprint

    Colitis
    MicroRNAs
    Microspheres
    Regeneration
    Colon
    Epithelium
    Dextran Sulfate
    Ulcerative Colitis
    Knockout Mice
    Organoids
    Crohn Disease
    Cytokine Receptors
    Sulfonic Acids
    Messenger RNA
    Colorectal Neoplasms
    Proteins
    Epithelial Cells
    Lactalbumin
    Interleukin-7
    Enema

    Keywords

    • Gene Regulation
    • IBD
    • Nanoparticle Delivery System
    • Posttranscriptional Processing

    ASJC Scopus subject areas

    • Hepatology
    • Gastroenterology

    Cite this

    MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis in Mice. / Tian, Yuhua; Xu, Jiuzhi; Li, Yuan; Zhao, Ran; Du, Sujuan; Lv, Cong; Wu, Wei; Liu, Ruiqi; Sheng, Xiaole; Song, Yongli; Bi, Xueyun; Li, Guilin; Li, Mengzhen; Wu, Xi; Lou, Pengbo; You, Huiwen; Cui, Wei; Sun, Jinyue; Shuai, Jianwei; Ren, Fazheng; Zhang, Bing; Guo, Mingzhou; Hou, Xiaohua; Wu, Kaichun; Xue, Lixiang; Zhang, Hongquan; Plikus, Maksim V.; Cong, Yingzi; Lengner, Christopher J.; Liu, Zhanju; Yu, Zhengquan.

    In: Gastroenterology, Vol. 156, No. 8, 01.06.2019, p. 2281-2296.e6.

    Research output: Contribution to journalArticle

    Tian, Y, Xu, J, Li, Y, Zhao, R, Du, S, Lv, C, Wu, W, Liu, R, Sheng, X, Song, Y, Bi, X, Li, G, Li, M, Wu, X, Lou, P, You, H, Cui, W, Sun, J, Shuai, J, Ren, F, Zhang, B, Guo, M, Hou, X, Wu, K, Xue, L, Zhang, H, Plikus, MV, Cong, Y, Lengner, CJ, Liu, Z & Yu, Z 2019, 'MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis in Mice', Gastroenterology, vol. 156, no. 8, pp. 2281-2296.e6. https://doi.org/10.1053/j.gastro.2019.02.023
    Tian, Yuhua ; Xu, Jiuzhi ; Li, Yuan ; Zhao, Ran ; Du, Sujuan ; Lv, Cong ; Wu, Wei ; Liu, Ruiqi ; Sheng, Xiaole ; Song, Yongli ; Bi, Xueyun ; Li, Guilin ; Li, Mengzhen ; Wu, Xi ; Lou, Pengbo ; You, Huiwen ; Cui, Wei ; Sun, Jinyue ; Shuai, Jianwei ; Ren, Fazheng ; Zhang, Bing ; Guo, Mingzhou ; Hou, Xiaohua ; Wu, Kaichun ; Xue, Lixiang ; Zhang, Hongquan ; Plikus, Maksim V. ; Cong, Yingzi ; Lengner, Christopher J. ; Liu, Zhanju ; Yu, Zhengquan. / MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis in Mice. In: Gastroenterology. 2019 ; Vol. 156, No. 8. pp. 2281-2296.e6.
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    title = "MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis in Mice",
    abstract = "Background & Aims: Levels of microRNA 31 (MIR31) are increased in intestinal tissues from patients with inflammatory bowel diseases and colitis-associated neoplasias. We investigated the effects of this microRNA on intestinal inflammation by studying mice with colitis. Methods: We obtained colon biopsy samples from 82 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 34 healthy individuals (controls) at Shanghai Tenth People's Hospital. MIR31- knockout mice and mice with conditional disruption of Mir31 specifically in the intestinal epithelium (MIR31 conditional knockouts) were given dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. We performed chromatin immunoprecipitation and luciferase assays to study proteins that regulate expression of MIR31, including STAT3 and p65, in LOVO colorectal cancer cells and organoids derived from mouse colon cells. Partially hydrolyzed alpha-lactalbumin was used to generate peptosome nanoparticles, and MIR31 mimics were loaded onto their surface using electrostatic adsorption. Peptosome–MIR31 mimic particles were encapsulated into oxidized konjac glucomannan (OKGM) microspheres, which were administered by enema into the large intestines of mice with DSS-induced colitis. Intestinal tissues were collected and analyzed by histology and immunohistochemistry. Results: Levels of MIR31 were increased in inflamed mucosa from patients with CD or UC, and from mice with colitis, compared with controls. STAT3 and nuclear factor-κB activated transcription of MIR31 in colorectal cancer cells and organoids in response to tumor necrosis factor and interleukin (IL)6. MIR31-knockout and conditional-knockout mice developed more severe colitis in response to DSS and TNBS, with increased immune responses, compared with control mice. MIR31 bound to 3ʹ untranslated regions of Il17ra and Il7r messenger RNAs (RNAs) (which encode receptors for the inflammatory cytokines IL17 and IL7) and Il6st mRNA (which encodes GP130, a cytokine signaling protein). These mRNAs and proteins were greater in MIR31-knockout mice with colitis, compared with control mice; MIR31 and MIR31 mimics inhibited their expression. MIR31 also promoted epithelial regeneration by regulating the WNT and Hippo signaling pathways. OKGM peptosome–MIR31 mimic microspheres localized to colonic epithelial cells in mice with colitis; they reduced the inflammatory response, increased body weight and colon length, and promoted epithelial cell proliferation. Conclusions: MIR31, increased in colon tissues from patients with CD or UC, reduces the inflammatory response in colon epithelium of mice by preventing expression of inflammatory cytokine receptors (Il7R and Il17RA) and signaling proteins (GP130). MIR31 also regulates the WNT and Hippo signaling pathways to promote epithelial regeneration following injury. OKGM peptosome–MIR31 microspheres localize to the colon epithelium of mice to reduce features of colitis. Transcript Profiling: GSE123556",
    keywords = "Gene Regulation, IBD, Nanoparticle Delivery System, Posttranscriptional Processing",
    author = "Yuhua Tian and Jiuzhi Xu and Yuan Li and Ran Zhao and Sujuan Du and Cong Lv and Wei Wu and Ruiqi Liu and Xiaole Sheng and Yongli Song and Xueyun Bi and Guilin Li and Mengzhen Li and Xi Wu and Pengbo Lou and Huiwen You and Wei Cui and Jinyue Sun and Jianwei Shuai and Fazheng Ren and Bing Zhang and Mingzhou Guo and Xiaohua Hou and Kaichun Wu and Lixiang Xue and Hongquan Zhang and Plikus, {Maksim V.} and Yingzi Cong and Lengner, {Christopher J.} and Zhanju Liu and Zhengquan Yu",
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    TY - JOUR

    T1 - MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis in Mice

    AU - Tian, Yuhua

    AU - Xu, Jiuzhi

    AU - Li, Yuan

    AU - Zhao, Ran

    AU - Du, Sujuan

    AU - Lv, Cong

    AU - Wu, Wei

    AU - Liu, Ruiqi

    AU - Sheng, Xiaole

    AU - Song, Yongli

    AU - Bi, Xueyun

    AU - Li, Guilin

    AU - Li, Mengzhen

    AU - Wu, Xi

    AU - Lou, Pengbo

    AU - You, Huiwen

    AU - Cui, Wei

    AU - Sun, Jinyue

    AU - Shuai, Jianwei

    AU - Ren, Fazheng

    AU - Zhang, Bing

    AU - Guo, Mingzhou

    AU - Hou, Xiaohua

    AU - Wu, Kaichun

    AU - Xue, Lixiang

    AU - Zhang, Hongquan

    AU - Plikus, Maksim V.

    AU - Cong, Yingzi

    AU - Lengner, Christopher J.

    AU - Liu, Zhanju

    AU - Yu, Zhengquan

    PY - 2019/6/1

    Y1 - 2019/6/1

    N2 - Background & Aims: Levels of microRNA 31 (MIR31) are increased in intestinal tissues from patients with inflammatory bowel diseases and colitis-associated neoplasias. We investigated the effects of this microRNA on intestinal inflammation by studying mice with colitis. Methods: We obtained colon biopsy samples from 82 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 34 healthy individuals (controls) at Shanghai Tenth People's Hospital. MIR31- knockout mice and mice with conditional disruption of Mir31 specifically in the intestinal epithelium (MIR31 conditional knockouts) were given dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. We performed chromatin immunoprecipitation and luciferase assays to study proteins that regulate expression of MIR31, including STAT3 and p65, in LOVO colorectal cancer cells and organoids derived from mouse colon cells. Partially hydrolyzed alpha-lactalbumin was used to generate peptosome nanoparticles, and MIR31 mimics were loaded onto their surface using electrostatic adsorption. Peptosome–MIR31 mimic particles were encapsulated into oxidized konjac glucomannan (OKGM) microspheres, which were administered by enema into the large intestines of mice with DSS-induced colitis. Intestinal tissues were collected and analyzed by histology and immunohistochemistry. Results: Levels of MIR31 were increased in inflamed mucosa from patients with CD or UC, and from mice with colitis, compared with controls. STAT3 and nuclear factor-κB activated transcription of MIR31 in colorectal cancer cells and organoids in response to tumor necrosis factor and interleukin (IL)6. MIR31-knockout and conditional-knockout mice developed more severe colitis in response to DSS and TNBS, with increased immune responses, compared with control mice. MIR31 bound to 3ʹ untranslated regions of Il17ra and Il7r messenger RNAs (RNAs) (which encode receptors for the inflammatory cytokines IL17 and IL7) and Il6st mRNA (which encodes GP130, a cytokine signaling protein). These mRNAs and proteins were greater in MIR31-knockout mice with colitis, compared with control mice; MIR31 and MIR31 mimics inhibited their expression. MIR31 also promoted epithelial regeneration by regulating the WNT and Hippo signaling pathways. OKGM peptosome–MIR31 mimic microspheres localized to colonic epithelial cells in mice with colitis; they reduced the inflammatory response, increased body weight and colon length, and promoted epithelial cell proliferation. Conclusions: MIR31, increased in colon tissues from patients with CD or UC, reduces the inflammatory response in colon epithelium of mice by preventing expression of inflammatory cytokine receptors (Il7R and Il17RA) and signaling proteins (GP130). MIR31 also regulates the WNT and Hippo signaling pathways to promote epithelial regeneration following injury. OKGM peptosome–MIR31 microspheres localize to the colon epithelium of mice to reduce features of colitis. Transcript Profiling: GSE123556

    AB - Background & Aims: Levels of microRNA 31 (MIR31) are increased in intestinal tissues from patients with inflammatory bowel diseases and colitis-associated neoplasias. We investigated the effects of this microRNA on intestinal inflammation by studying mice with colitis. Methods: We obtained colon biopsy samples from 82 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 34 healthy individuals (controls) at Shanghai Tenth People's Hospital. MIR31- knockout mice and mice with conditional disruption of Mir31 specifically in the intestinal epithelium (MIR31 conditional knockouts) were given dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. We performed chromatin immunoprecipitation and luciferase assays to study proteins that regulate expression of MIR31, including STAT3 and p65, in LOVO colorectal cancer cells and organoids derived from mouse colon cells. Partially hydrolyzed alpha-lactalbumin was used to generate peptosome nanoparticles, and MIR31 mimics were loaded onto their surface using electrostatic adsorption. Peptosome–MIR31 mimic particles were encapsulated into oxidized konjac glucomannan (OKGM) microspheres, which were administered by enema into the large intestines of mice with DSS-induced colitis. Intestinal tissues were collected and analyzed by histology and immunohistochemistry. Results: Levels of MIR31 were increased in inflamed mucosa from patients with CD or UC, and from mice with colitis, compared with controls. STAT3 and nuclear factor-κB activated transcription of MIR31 in colorectal cancer cells and organoids in response to tumor necrosis factor and interleukin (IL)6. MIR31-knockout and conditional-knockout mice developed more severe colitis in response to DSS and TNBS, with increased immune responses, compared with control mice. MIR31 bound to 3ʹ untranslated regions of Il17ra and Il7r messenger RNAs (RNAs) (which encode receptors for the inflammatory cytokines IL17 and IL7) and Il6st mRNA (which encodes GP130, a cytokine signaling protein). These mRNAs and proteins were greater in MIR31-knockout mice with colitis, compared with control mice; MIR31 and MIR31 mimics inhibited their expression. MIR31 also promoted epithelial regeneration by regulating the WNT and Hippo signaling pathways. OKGM peptosome–MIR31 mimic microspheres localized to colonic epithelial cells in mice with colitis; they reduced the inflammatory response, increased body weight and colon length, and promoted epithelial cell proliferation. Conclusions: MIR31, increased in colon tissues from patients with CD or UC, reduces the inflammatory response in colon epithelium of mice by preventing expression of inflammatory cytokine receptors (Il7R and Il17RA) and signaling proteins (GP130). MIR31 also regulates the WNT and Hippo signaling pathways to promote epithelial regeneration following injury. OKGM peptosome–MIR31 microspheres localize to the colon epithelium of mice to reduce features of colitis. Transcript Profiling: GSE123556

    KW - Gene Regulation

    KW - IBD

    KW - Nanoparticle Delivery System

    KW - Posttranscriptional Processing

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