Browse > Article
http://dx.doi.org/10.4062/biomolther.2020.112

Contributions of HO-1-Dependent MAPK to Regulating Intestinal Barrier Disruption  

Zhang, Zhenling (Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University)
Zhang, Qiuping (Department of Pathology, the First Affiliated Hospital of Dalian Medical University)
Li, Fang (Department of Immunology, Dalian Medical University)
Xin, Yi (Department of Biochemistry and Molecular Biology, Dalian Medical University)
Duan, Zhijun (Department of Gastroenterology, the First Affiliated Hospital of Dalian Medical University)
Publication Information
Biomolecules & Therapeutics / v.29, no.2, 2021 , pp. 175-183 More about this Journal
Abstract
The mitogen-activated protein kinase (MAPK) pathway controls intestinal epithelial barrier permeability by regulating tight junctions (TJs) and epithelial cells damage. Heme oxygenase-1 (HO-1) and carbon monoxide (CO) protect the intestinal epithelial barrier function, but the molecular mechanism is not yet clarified. MAPK activation and barrier permeability were studied using monolayers of Caco-2 cells treated with tissue necrosis factor α (TNF-α) transfected with FUGW-HO-1 or pLKO.1-sh-HO-1 plasmid. Intestinal mucosal barrier permeability and MAPK activation were also investigated using carbon tetrachloride (CCl4) administration with CoPP (a HO-1 inducer), ZnPP (a HO-1 inhibitor), CO releasing molecule 2 (CORM-2), or inactived-CORM-2-treated wild-type mice and mice with HO-1 deficiency in intestinal epithelial cells. TNF-α increased epithelial TJ disruption and cleaved caspase-3 expression, induced ERK, p38, and JNK phosphorylation. In addition, HO-1 blocked TNF-α-induced increase in epithelial TJs disruption, cleaved caspase-3 expression, as well as ERK, p38, and JNK phosphorylation in an HO-1-dependent manner. CoPP and CORM-2 directly ameliorated intestinal mucosal injury, attenuated TJ disruption and cleaved caspase-3 expression, and inhibited epithelial ERK, p38, and JNK phosphorylation after chronic CCl4 injection. Conversely, ZnPP completely reversed these effects. Furthermore, mice with intestinal epithelial HO-1 deficient exhibited a robust increase in mucosal TJs disruption, cleaved caspase-3 expression, and MAPKs activation as compared to the control group mice. These data demonstrated that HO-1-dependent MAPK signaling inhibition preserves the intestinal mucosal barrier integrity by abrogating TJ dysregulation and epithelial cell damage. The differential targeting of gut HO-1-MAPK axis leads to improved intestinal disease therapy.
Keywords
HO-1; Intestinal barrier function; Tight junction; MAPK; Inflammatory bowel disease;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Li, Y., Liu, M., Gao, S., Cai, L., Zhang, Q., Yan, S., Liu, G. and Ji, B. (2019) Cold-inducible RNA-binding protein maintains intestinal barrier during deep hypothermic circulatory arrest. Interact. Cardiovasc. Thorac. Surg. 29, 583-591.   DOI
2 Liu, X., Zhu, Q., Zhang, M., Yin, T., Xu, R., Xiao, W., Wu, J., Deng, B., Gao, X., Gong, W., Lu, G. and Ding, Y. (2018) Isoliquiritigenin ameliorates acute pancreatitis in mice via inhibition of oxidative stress and modulation of the Nrf2/HO-1 pathway. Oxid. Med. Cell. Longev. 2018, 7161592.   DOI
3 Meir, M., Burkard, N., UngewiB, H., Diefenbacher, M., Flemming, S., Kannapin, F., Germer, C. T., Schweinlin, M., Metzger, M., Waschke, J. and Schlegel, N. (2019) Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease. J. Clin. Invest. 129, 2824-2840.   DOI
4 Mishra, M., Tiwari, S. and Gomes, A. V. (2017) Protein purification and analysis: next generation western blotting techniques. Expert Rev. Proteomics 14, 1037-1053.   DOI
5 Nighot, P. and Ma, T. (2020) Endocytosis of intestinal tight junction proteins: in time and space. Inflamm. Bowel Dis. doi: 10.1093/ibd/izaa141 [Online ahead of print].   DOI
6 Naito, Y., Takagi, T., Uchiyama, K. and Yoshikawa, T. (2011) Heme oxygenase-1: a novel therapeutic target for gastrointestinal diseases. J. Clin. Biochem. Nutr. 48, 126-133.   DOI
7 Otani, S., Oami, T., Yoseph, B. P., Klingensmith, N. J., Chen, C. W., Liang, Z. and Coopersmith, C. M. (2020) Overexpression of BCL-2 in the intestinal epithelium prevents sepsis-induced gut barrier dysfunction via altering tight junction protein expression. Shock 54, 330-336.   DOI
8 Jin, Y. and Blikslager, A. T. (2020) The regulation of intestinal mucosal barrier bymyosin light chain kinase/Rho kinases. Int. J. Mol. Sci. 21, E3550.
9 Wu, Y., Wu, B., Zhang, Z., Lu, H., Fan, C., Qi, Q., Gao, Y., Li, H., Feng, C., Zuo, J. and Tang, W. (2020) Heme protects intestinal mucosal barrier in DSS-induced colitis through regulating macrophage polarization in both HO-1-dependent and HO-1-independent way. FASEB J. 34, 8028-8043.   DOI
10 Xue, J. and Habtezion, A. (2014) Carbon monoxide-based therapy amelioratesacute pancreatitis via TLR4 inhibition. J. Clin. Invest. 124, 437-447.   DOI
11 Xiong, W., Huang, J., Li, X., Zhang, Z., Jin, M., Wang, J., Xu, Y. and Wang, Z. (2020) Icariin and its phosphorylated derivatives alleviate intestinal epithelial barrier disruption caused by enterotoxigenic Escherichia coli through modulate p38 MAPK in vivo and in vitro. FASEB J. 34, 1783-1801.   DOI
12 Yang, L., Liu, G., Lian, K., Qiao, Y., Zhang, B., Zhu, X., Luo, Y., Shang, Y. and Gu, X. L. (2019) Dietary leonurine hydrochloride supplementation attenuates lipopolysaccharide challenge-induced intestinal inflammation and barrier dysfunction by inhibiting the NF-κB/MAPK signaling pathway in broilers. J. Anim. Sci. 97, 1679-1692.   DOI
13 Cho, R. L., Lin, W. N., Wang, C. Y., Yang, C. C., Hsiao, L. D., Lin, C. C. and Yang, C. M. (2018) Heme oxygenase-1 induction by rosiglitazone via PKCα/AMPKα/p38MAPKα/SIRT1/PPARγ pathway suppresses lipopolysaccharide-mediated pulmonary inflammation. Biochem. Pharmacol. 148, 222-237.   DOI
14 Zhan, C. Y., Chen, D., Luo, J. L., Shi, Y. H. and Zhang, Y. P. (2018) Protective role of down-regulated microRNA-31 on intestinal barrier dysfunction through inhibition of NF-κB/HIF-1α pathway by binding to HMOX1 in rats with sepsis. Mol. Med. 24, 55.   DOI
15 Zhang, L. J., Zhang, Z. L., Liu, B. J., Jin, Y. L., Tian, Y., Xin, Y. and Duan, Z. J. (2017) The protective effect of heme oxygenase-1 against intestinal barrier dysfunction in cholestatic liver injury is associated with NF-κB inhibition. Mol. Med. 23, 215-224.   DOI
16 Zhuang, S., Zhong, J., Bian, Y. F., Fan, Y., Chen, Q., Liu, P. and Liu, Z. (2019) Rhein ameliorates lipopolysaccharide-induced intestinal barrier injury viamodulation of Nrf2 and MAPKs. Life Sci. 216, 168-175.   DOI
17 Albillos, A., de Gottardi, A. and Rescigno, M. (2020) The gut-liver axis in liver disease: pathophysiological basis for therapy. J. Hepatol. 72, 558-577.   DOI
18 Borgonetti, V., Cocetta, V., Biagi, M., Carnevali, I., Governa, P. and Montopoli, M. (2020) Anti-inflammatory activity of a fixed combination of probiotics and herbal extract in an in vitro model of intestinal inflammation by stimulating Caco-2 cells with LPS-conditioned THP-1 cells medium. Minerva Pediatr. doi: 10.23736/S0026-4946.20.05765-5 [Online ahead of print].   DOI
19 Bakhautdin, B., Das, D., Mandal, P., Roychowdhury, S., Danner, J., Bush, K., Pollard, K., Kaspar, J. W., Li, W., Salomon, R. G., McMullen, M. R. and Nagy, L. E. (2014) Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice. J. Hepatol. 61, 1029-1037.   DOI
20 Chi, J. H., Kim, Y. H., Sohn, D. H., Seo, G. S. and Lee, S. H. (2018) Ameliorativeeffect of Alnus japonica ethanol extract on colitis through the inhibition of inflammatory responses and attenuation of intestinal barrier disruption in vivo and in vitro. Biomed. Pharmacother. 108, 1767-1774.   DOI
21 Chen, Y., Park, H. J., Park, J., Song, H. C., Ryter, S. W., Surh, Y. J., Kim, U. H., Joe, Y. and Chung, H. T. (2019) Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and parkin expression. FASEB J. 33, 13905-13919.   DOI
22 Seo, G. S., Jiang, W. Y., Park, P. H., Sohn, D. H., Cheon, J. H. and Lee, S. H. (2014) Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction. Biochem. Pharmacol. 90, 115-125.   DOI
23 Onyiah, J. C., Sheikh, S. Z., Maharshak, N., Steinbach, E. C., Russo, S. M., Kobayashi, T., Mackey, L. C., Hansen, J. J., Moeser, A. J., Rawls, J. F., Borst, L. B., Otterbein, L. E. and Plevy, S. E. (2013) Carbon monoxide and heme oxygenase-1 prevent intestinal inflammation in mice by promoting bacterial clearance. Gastroenterology 144, 789-798.   DOI
24 Petecchia, L., Sabatini, F., Usai, C., Caci, E., Varesio, L. and Rossi, G. A. (2012) Cytokines induce tight junction disassembly in airway cells via an EGFR-dependent MAPK/ERK1/2-pathway. Lab. Invest. 92, 1140-1148.   DOI
25 Ran, X., Li, Y. H., Chen, G. X., Fu, S., He, D., Huang, B., Wei, L., Lin, Y., Guo, Y. and Hu, G. (2018) Farrerol ameliorates TNBS-induced colonic inflammation by inhibiting ERK1/2, JNK1/2, and NF-κB signaling pathway. Int. J. Mol. Sci. 19, 2037.   DOI
26 Slifer, Z. M. and Blikslager, A. T. (2020) The integral role of tight junction proteins in the repair of injured intestinal epithelium. Int. J. Mol. Sci. 21, 972.   DOI
27 Stefanson, A. L. and Bakovic, M. (2018) Falcarinol is a potent inducer of heme oxygenase-1 and was more effective than sulforaphane in attenuating intestinal inflammation at diet-achievable doses. Oxid. Med. Cell. Longev. 2018, 3153527.   DOI
28 Su, L., Nalle, S. C., Shen, L., Turner, E. S., Singh, G., Breskin, L. A., Khramtsova, E. A., Khramtsova, G., Tsai, P. Y., Fu, Y. X., Abraham, C. and Turner, J. R. (2013) TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. Gastroenterology 145, 407-415.   DOI
29 Du, J., Chen, Y., Shi, Y., Liu, T., Cao, Y., Tang, Y., Ge, X., Nie, H., Zheng, C. and Li, Y. C. (2015) 1,25-Dihydroxyvitamin D protects intestinal epithelial barrier by regulating the myosin light chain kinase signaling pathway. Inflamm. Bowel Dis. 21, 2495-2506.   DOI
30 Chen, P., Starkel, P., Turner, J. R., Ho, S. B. and Schnabl, B. (2015) Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice. Hepatology 61, 883-894.   DOI
31 De Backer, O., Elinck, E., Blanckaert, B., Leybaert, L., Motterlini, R. and Lefebvre, R. A. (2009) Water-soluble CO-releasing molecules reduce the development of postoperative ileus via modulation of MAPK/HO-1 signalling and reduction of oxidative stress. Gut 58, 347-356.   DOI
32 Feng, Y. and Teitelbaum, D. H. (2013) Tumour necrosis factor-α-induced loss of intestinal barrier function requires TNFR1 and TNFR2 signalling in a mouse model of total parenteral nutrition. J. Physiol. 591, 3709-3723.   DOI
33 Hua, X., Chi, W., Su, L., Li, J., Zhang, Z. and Yuan, X. (2017) ROSinduced oxidative injury involved in pathogenesis of fungal keratitis via p38MAPK activation. Sci. Rep. 7, 10421.   DOI
34 Hartmann, P., Haimerl, M., Mazagova, M., Brenner, D. A. and Schnabl, B. (2012) Toll-like receptor 2-mediated intestinal injury and enteric tumor necrosis factor receptor I contribute to liver fibrosis in mice. Gastroenterology 143, 1330-1340.   DOI
35 Hall, C. H. T., Lee, J. S., Murphy, E. M., Gerich, M. E., Dran, R., Glover, L. E., Abdulla, Z. I., Skelton, M. R. and Colgan, S. P. (2020) Creatine transporter, reduced in colon tissues from patients with inflammatory bowel diseases, regulates energy balance in intestinal epithelial cells, epithelial integrity, and barrier function. Gastroenterology doi: 10.1053/j.gastro.2020.05.033 [Online ahead of print].   DOI
36 Tabat, M. W., Marques, T. M., Markgren, M., Lofvendahl, L., Brummer, R. J. and Wall, R. (2020) Acute effects of butyrate on induced hyperpermeability and tight junction protein expression in human colonic tissues. Biomolecules 10, 766.   DOI
37 Song, W. B., Wang, Y. Y., Meng, F. S., Zhang, Q. H., Zeng, J. Y., Xiao, L. P., Yu, X. P., Peng, D. D., Su, L., Xiao, B. and Zhang, Z. S. (2010) Curcumin protects intestinal mucosal barrier function of rat enteritis via activation of MKP-1 and attenuation of p38 and NF-κB activation. PLoS ONE 5, e12969.   DOI
38 Sun, L. H., Xu, C., Chen, G. Q., Yu, M., Yang, S., Qiu, Y., Peng, K., Wang, W., Xiao, W. and Yang, H. (2015) A novel role of OS-9 in the maintenance of intestinal barrier function from hypoxia-induced injury via p38-dependent pathway. Int. J. Biol. Sci. 11, 664-671.   DOI
39 Shao, T., Zhao, C. Q., Li, F. Y., Gu, Z. L., Liu, L. M., Zhang, L. H., Wang, Y. H., He, L. Q., Liu, Y. H., Liu, Q., Chen, Y. P., Donde, H., Wang, R., Jala, V. R., Barve, S., Chen, S. Y., Zhang, X., Chen, Y. P., McClain, C. J. and Wenke, F. (2018) Intestinal HIF-1α deletion exacerbates alcoholic liver disease by inducing intestinal dysbiosis and barrier dysfunction. J. Hepatol. 69, 886-895.   DOI
40 Vijayan, V., Wagener, F. A. D. T. G. and Immenschuh, S. (2018) The macrophage heme-heme oxygenase-1 system and its role in inflammation. Biochem. Pharmacol. 153, 159-167.   DOI
41 Wang, H., Zhang, S., Zhao, H., Qin, H., Zhang, J., Dong, J., Zhang, H., Liu, X., Zhao, Z., Zhao, Y., Shao, M., Wu, F. and Zhang, W. (2020) Carbon monoxide inhibits the expression of proteins associated with intestinal mucosal pyroptosis in a rat model of sepsis induced by cecal ligation and puncture. Med. Sci. Monit. 26, e920668.
42 Wang, H., Liu, Y., Shi, H., Wang, X., Zhu, H., Pi, D., Leng, W. and Li, S. (2017) Aspartate attenuates intestinal injury and inhibits TLR4 and NODs/NF-κB and p38 signaling in weaned pigs after LPS challenge. Eur. J. Nutr. 56, 1433-1443.   DOI