Mast cells-derived MiR-223 destroys intestinal barrier function by inhibition of CLDN8 expression in intestinal epithelial cells
Tóm tắt
Mast cells (MCs) have been found to play a critical role during development of inflammatory bowel disease (IBD) that characterized by dysregulation of inflammation and impaired intestinal barrier function. However, the function of MCs in IBD remains to be fully elucidated.
In our study, we used exosomes isolated from human mast cells-1 (HMCs-1) to culture with NCM460, HT-29 or CaCO2 of intestinal epithelial cells (IECs) to investigate the communication between MCs and IECs. We found that MCs-derived exosomes significantly increased intestinal epithelial permeability and destroyed intestinal barrier function, which is attributed to exosome-mediated functional miRNAs were transferred from HMCs-1 into IECs, leading to inhibit tight junction-related proteins expression, including tight junction proteins 1 (TJP1, ZO-1), Occludin (OCLN), Claudin 8 (CLDN8). Microarray and bioinformatic analysis have further revealed that a panel of miRNAs target different tight junction-related proteins. Interestingly, miR-223 is enriched in mast cell-derived exosome, which inhibit CLDN8 expression in IECs, while treatment with miR-223 inhibitor in HT-29 cells significantly reversed the inhibitory effect of HMCs-1-derived exosomes on CLDN 8 expression. Most importantly, enrichment of MCs accumulation in intestinal mucosa of patients with IBD compared with those healthy control.
These results indicated that enrichment of exosomal miR-223 from HMCs-1 inhibited CLDN8 expression, leading to destroy intestinal barrier function. These finding provided a novel insight of MCs as a new target for therapeutic treatment of IBD.
Từ khóa
Tài liệu tham khảo
Zhang S, Xu W, Wang H, Cao M, Li M, Zhao J et al (2019) Inhibition of CREB-mediated ZO-1 and activation of NF-kappaB-induced IL-6 by colonic epithelial MCT4 destroys intestinal barrier function. Cell Prolif. 52(6):e12673.
He Z, Song J, Hua J, Yang M, Ma Y, Yu T, et al. Mast cells are essential intermediaries in regulating IL-33/ST2 signaling for an immune network favorable to mucosal healing in experimentally inflamed colons. Cell Death Dis. 2018;9(12):1173.
Nebot-Vivinus M, Harkat C, Bzioueche H, Cartier C, Plichon-Dainese R, Moussa L, et al. Multispecies probiotic protects gut barrier function in experimental models. World J Gastroenterol. 2014;20(22):6832–43.
Saadalla AM, Osman A, Gurish MF, Dennis KL, Blatner NR, Pezeshki A, et al. Mast cells promote small bowel cancer in a tumor stage-specific and cytokine-dependent manner. Proc Natl Acad Sci USA. 2018;115(7):1588–92.
Potts RA, Tiffany CM, Pakpour N, Lokken KL, Tiffany CR, Cheung K, et al. Mast cells and histamine alter intestinal permeability during malaria parasite infection. Immunobiology. 2016;221(3):468–74.
Eissmann MF, Dijkstra C, Jarnicki A, Phesse T, Brunnberg J, Poh AR, et al. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun. 2019;10(1):2735.
Xie L, Liu T, Yao H, Wu L, Qiu W, Chen B, et al. Autoimmune inflammatory meningoencephalitis in a patient negative for glial fibrillary acidic protein-specific immunoglobulin G. Mult Scler Relat Disord. 2019;28:167–71.
Cheung KL, Jarrett R, Subramaniam S, Salimi M, Gutowska-Owsiak D, Chen YL, et al. Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a. J Exp Med. 2016;213(11):2399–412.
Skokos D, Botros HG, Demeure C, Morin J, Peronet R, Birkenmeier G, et al. Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol. 2003;170(6):3037–45.
Laukoetter MG, Nava P, Lee WY, Severson EA, Capaldo CT, Babbin BA, et al. JAM-A regulates permeability and inflammation in the intestine in vivo. J Exp Med. 2007;204(13):3067–76.
Gunzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93(2):525–69.
Takaki Y, Hirai S, Manabe N, Izumi Y, Hirose T, Nakaya M, et al. Dynamic changes in protein components of the tight junction during liver regeneration. Cell Tissue Res. 2001;305(3):399–409.
Zeissig S, Burgel N, Gunzel D, Richter J, Mankertz J, Wahnschaffe U, et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut. 2007;56(1):61–72.
Wang H, Chao K, Ng SC, Bai AH, Yu Q, Yu J, Li M, Cui Y, Chen M, Hu JF, Zhang S. Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease. Genome Biol. 2016;17:58.
Clark PM, Dawany N, Dampier W, Byers SW, Pestell RG, Tozeren A. Bioinformatics analysis reveals transcriptome and microRNA signatures and drug repositioning targets for IBD and other autoimmune diseases. Inflamm Bowel Dis. 2012;18(12):2315–33.
Wu CP, Bi YJ, Liu DM, Wang LY. Hsa-miR-375 promotes the progression of inflammatory bowel disease by upregulating TLR4. Eur Rev Med Pharmacol Sci. 2019;23(17):7543–9.
Pei XF, Cao LL, Huang F, Qiao X, Yu J, Ye H, et al. Role of miR-22 in intestinal mucosa tissues and peripheral blood CD4+ T cells of inflammatory bowel disease. Pathol Res Pract. 2018;214(8):1095–104.
Li M, Zhang S, Qiu Y, He Y, Chen B, Mao R, et al. Upregulation of miR-665 promotes apoptosis and colitis in inflammatory bowel disease by repressing the endoplasmic reticulum stress components XBP1 and ORMDL3. Cell Death Dis. 2017;8(3):e2699.
Xu W, Zhang Z, Zou K, Cheng Y, Yang M, Chen H, et al. MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell Death Dis. 2017;8(5):e2761.
Xiao H, Lasser C, Shelke GV, Wang J, Radinger M, Lunavat TR, et al. Mast cell exosomes promote lung adenocarcinoma cell proliferation—role of KIT-stem cell factor signaling. Cell Commun Signal. 2014;12:64.
Zhou M, Chen J, Zhou L, Chen W, Ding G, Cao L. Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cell Immunol. 2014;292(1–2):65–9.
Chevillet JR, Kang Q, Ruf IK, Briggs HA, Vojtech LN, Hughes SM, et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci USA. 2014;111(41):14888–93.
Haneklaus M, Gerlic M, O’Neill LA, Masters SL. miR-223: infection, inflammation and cancer. J Intern Med. 2013;274(3):215–26.
Josse J, Velard F, Mechiche Alami S, Brun V, Guillaume C, Kerdjoudj H, et al. Increased internalization of Staphylococcus aureus and cytokine expression in human Wharton’s jelly mesenchymal stem cells. Biomed Mater Eng. 2014;24(1 Suppl):27–35.
Yu DS, Wang YS, Bi YL, Guo ZP, Yuan YJ, Tong SM, et al. Salvianolic acid A ameliorates the integrity of blood-spinal cord barrier via miR-101/Cul3/Nrf2/HO-1 signaling pathway. Brain Res. 2017;1657:279–87.
Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25(4):501–15.
Zhao L, Wang P, Liu Y, Ma J, Xue Y. miR-34c regulates the permeability of blood-tumor barrier via MAZ-mediated expression changes of ZO-1, occludin, and claudin-5. J Cell Physiol. 2015;230(3):716–31.
Ma J, Yao Y, Wang P, Liu Y, Zhao L, Li Z, Li Z, Xue Y. MiR-181a regulates blood-tumor barrier permeability by targeting Kruppel-like factor 6. J Cereb Blood Flow Metab. 2014;34:1826–36.
Bischoff SC, Kramer S. Human mast cells, bacteria, and intestinal immunity. Immunol Rev. 2007;217:329–37.
Ravanbakhsh N, Kesavan A. The role of mast cells in pediatric gastrointestinal disease. Ann Gastroenterol. 2019;32(4):338–45.
De Zuani M, Dal Secco C, Frossi B. Mast cells at the crossroads of microbiota and IBD. Eur J Immunol. 2018;48(12):1929–37.
Wilcock A, Bahri R, Bulfone-Paus S, Arkwright PD. Mast cell disorders: from infancy to maturity. Allergy. 2019;74(1):53–63.
Lennon EM, Borst LB, Edwards LL, Moeser AJ. Mast cells exert anti-inflammatory effects in an IL10(−/−) model of spontaneous colitis. Mediators Inflamm. 2018;2018:7817360.
Kannen V, Sakita JY, Carneiro ZA, Bader M, Alenina N, Teixeira RR, et al. Mast cells and serotonin synthesis modulate chagas disease in the colon: clinical and experimental evidence. Dig Dis Sci. 2018;63(6):1473–84.
Wilcz-Villega EM, McClean S, O’Sullivan MA. Mast cell tryptase reduces junctional adhesion molecule-A (JAM-A) expression in intestinal epithelial cells: implications for the mechanisms of barrier dysfunction in irritable bowel syndrome. Am J Gastroenterol. 2013;108(7):1140–51.
Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010;73(10):1907–20.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.
Al-Nedawi K, Szemraj J, Cierniewski CS. Mast cell-derived exosomes activate endothelial cells to secrete plasminogen activator inhibitor type 1. Arterioscler Thromb Vasc Biol. 2005;25(8):1744–9.
Zhang L, Zhang F, He DK, Fan XM, Shen J. MicroRNA-21 is upregulated during intestinal barrier dysfunction induced by ischemia reperfusion. Kaohsiung J Med Sci. 2018;34:556–63.
Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, Wu CY, Kuo PL. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017;36:4929–42.
Burek M, Konig A, Lang M, Fiedler J, Oerter S, Roewer N, Bohnert M, Thal SC, Blecharz-Lang KG, Woitzik J, Thum T, Forster CY. Hypoxia-induced MicroRNA-212/132 alter blood-brain barrier integrity through inhibition of tight junction-associated proteins in human and mouse brain microvascular endothelial cells. Transl Stroke Res. 2019;10:672–83.
Tang Y, Zhang L, Forsyth CB, Shaikh M, Song S, Keshavarzian A. The role of miR-212 and iNOS in alcohol-induced intestinal barrier dysfunction and steatohepatitis. Alcohol Clin Exp Res. 2015;39:1632–41.
Ge X, Han Z, Chen F, Wang H, Zhang B, Jiang R, Lei P, Zhang J. MiR-21 alleviates secondary blood-brain barrier damage after traumatic brain injury in rats. Brain Res. 2015;1603:150–7.
Ge X, Huang S, Gao H, Han Z, Chen F, Zhang S, Wang Z, Kang C, Jiang R, Yue S, Lei P, Zhang J. miR-21-5p alleviates leakage of injured brain microvascular endothelial barrier in vitro through suppressing inflammation and apoptosis. Brain Res. 2016;1650:31–40.
Zhang L, Shen J, Cheng J, Fan X. MicroRNA-21 regulates intestinal epithelial tight junction permeability. Cell Biochem Funct. 2015;33:235–40.
Zhu Y, Wang W, Yuan T, Fu L, Zhou L, Lin G, Zhao S, Zhou H, Wu G, Wang J. MicroRNA-29a mediates the impairment of intestinal epithelial integrity induced by intrauterine growth restriction in pig. Am J Physiol Gastrointest Liver Physiol. 2017;312:G434–42.
Martinez C, Rodino-Janeiro BK, Lobo B, Stanifer ML, Klaus B, Granzow M, Gonzalez-Castro AM, Salvo-Romero E, Alonso-Cotoner C, Pigrau M, Roeth R, Rappold G, Huber W, Gonzalez-Silos R, Lorenzo J, de Torres I, Azpiroz F, Boulant S, Vicario M, Niesler B, Santos J. miR-16 and miR-125b are involved in barrier function dysregulation through the modulation of claudin-2 and cingulin expression in the jejunum in IBS with diarrhoea. Gut. 2017;66:1537–8.
Ye EA, Liu L, Steinle JJ. miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins. Vision Res. 2017;139:23–9.
Miao YS, Zhao YY, Zhao LN, Wang P, Liu YH, Ma J, Xue YX. MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5. Cell Signal. 2015;27:156–67.
Zhao YY, Zhao LN, Wang P, Miao YS, Liu YH, Wang ZH, Ma J, Li Z, Li ZQ, Xue YX. Overexpression of miR-18a negatively regulates myocyte enhancer factor 2D to increase the permeability of the blood-tumor barrier via Kruppel-like factor 4-mediated downregulation of zonula occluden-1, claudin-5, and occludin. J Neurosci Res. 2015;93:1891–902.
Miyata R, Kakuki T, Nomura K, Ohkuni T, Ogasawara N, Takano K, Konno T, Kohno T, Sawada N, Himi T, Kojima T. Poly(I:C) induced microRNA-146a regulates epithelial barrier and secretion of proinflammatory cytokines in human nasal epithelial cells. Eur J Pharmacol. 2015;761:375–82.
Cordes F, Bruckner M, Lenz P, Veltman K, Glauben R, Siegmund B, Hengst K, Schmidt MA, Cichon C, Bettenworth D. MicroRNA-320a strengthens intestinal barrier function and follows the course of experimental colitis. Inflamm Bowel Dis. 2016;22:2341–55.
Chen T, Xue H, Lin R, Huang Z. MiR-34c and PlncRNA1 mediated the function of intestinal epithelial barrier by regulating tight junction proteins in inflammatory bowel disease. Biochem Biophys Res Commun. 2017;486:6–13.
Wang L, Zhang R, Chen J, Wu Q, Kuang Z. Baicalin protects against TNF-alpha-induced injury by down-regulating miR-191a that targets the tight junction protein ZO-1 in IEC-6 cells. Biol Pharm Bull. 2017;40:435–43.
Yang J, Liu X, Yuan X, Wang Z. miR-99b promotes metastasis of hepatocellular carcinoma through inhibition of claudin 11 expression and may serve as a prognostic marker. Oncol Rep. 2015;34:1415–23.
Liu Z, Tian Y, Jiang Y, Chen S, Liu T, Moyer MP, Qin H, Zhou X. Protective effects of Let-7b on the expression of occludin by targeting P38 MAPK in preventing intestinal barrier dysfunction. Cell Physiol Biochem. 2018;45:343–55.
Zhao H, Zhao C, Dong Y, Zhang M, Wang Y, Li F, Li X, McClain C, Yang S, Feng W. Inhibition of miR122a by Lactobacillus rhamnosus GG culture supernatant increases intestinal occludin expression and protects mice from alcoholic liver disease. Toxicol Lett. 2015;234:194–200.
Zhu M, Fei L, Li D, Chen D. Correlation analysis of miR-122-5p and occludin with sperm density in oligospermia patients’ sperm. Clin Lab. 2019. https://doi.org/10.7754/Clin.Lab.2018.180814.
Zuo X, Lu J, Manaenko A, Qi X, Tang J, Mei Q, Xia Y, Hu Q. MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice. Exp Neurol. 2019;316:12–9.
Avalle L, Incarnato D, Savino A, Gai M, Marino F, Pensa S, Barbieri I, Stadler MB, Provero P, Oliviero S, Poli V. MicroRNAs-143 and -145 induce epithelial to mesenchymal transition and modulate the expression of junction proteins. Cell Death Differ. 2017;24:1750–60.
Bai Y, Zhang Y, Hua J, Yang X, Zhang X, Duan M, Zhu X, Huang W, Chao J, Zhou R, Hu G, Yao H. Silencing microRNA-143 protects the integrity of the blood-brain barrier: implications for methamphetamine abuse. Sci Rep. 2016;6:35642.
Mishra R, Singh SK. HIV-1 Tat C modulates expression of miRNA-101 to suppress VE-cadherin in human brain microvascular endothelial cells. J Neurosci. 2013;33:5992–6000.
Ge X, Li W, Huang S, Yin Z, Yang M, Han Z, Han Z, Chen F, Wang H, Lei P, Zhang J. Increased miR-21-3p in injured brain microvascular endothelial cells after traumatic brain injury aggravates blood-brain barrier damage by promoting cellular apoptosis and inflammation through targeting MAT2B. J Neurotrauma. 2019;36:1291–305.
Ma Q, Dasgupta C, Li Y, Huang L, Zhang L. MicroRNA-210 suppresses junction proteins and disrupts blood-brain barrier integrity in neonatal rat hypoxic-ischemic brain injury. Int J Mol Sci. 2017. https://doi.org/10.3390/ijms18071356.
Ma T, Xue YX. MiRNA-200b regulates RMP7-induced increases in blood-tumor barrier permeability by targeting RhoA and ROCKII. Front Mol Neurosci. 2016;9:9.
Shen Y, Zhou M, Yan J, Gong Z, Xiao Y, Zhang C, Du P, Chen Y. miR-200b inhibits TNF-alpha-induced IL-8 secretion and tight junction disruption of intestinal epithelial cells in vitro. Am J Physiol Gastrointest Liver Physiol. 2017;312:G123–32.
Zhao W, Wang P, Ma J, Liu YH, Li Z, Li ZQ, Wang ZH, Chen LY, Xue YX. MiR-34a regulates blood-tumor barrier function by targeting protein kinase Cepsilon. Mol Biol Cell. 2015;26:1786–96.
Zhang H, Zhang S, Zhang J, Liu D, Wei J, Fang W, Zhao W, Chen Y, Shang D. ZO-1 expression is suppressed by GM-CSF via miR-96/ERG in brain microvascular endothelial cells. J Cereb Blood Flow Metab. 2018;38:809–22.
Fang Z, He QW, Li Q, Chen XL, Baral S, Jin HJ, Zhu YY, Li M, Xia YP, Mao L, Hu B. MicroRNA-150 regulates blood-brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats. FASEB J. 2016;30:2097–107.
Yu T, Lu XJ, Li JY, Shan TD, Huang CZ, Ouyang H, Yang HS, Xu JH, Zhong W, Xia ZS, Chen QK. Overexpression of miR-429 impairs intestinal barrier function in diabetic mice by down-regulating occludin expression. Cell Tissue Res. 2016;366:341–52.
Liu W, Cai H, Lin M, Zhu L, Gao L, Zhong R, Bi S, Xue Y, Shang X. MicroRNA-107 prevents amyloid-beta induced blood-brain barrier disruption and endothelial cell dysfunction by targeting Endophilin-1. Exp Cell Res. 2016;343:248–57.
Chang CW, Yu JC, Hsieh YH, Yao CC, Chao JI, Chen PM, Hsieh HY, Hsiung CN, Chu HW, Shen CY, Cheng CW. MicroRNA-30a increases tight junction protein expression to suppress the epithelial-mesenchymal transition and metastasis by targeting Slug in breast cancer. Oncotarget. 2016;7:16462–78.