Hostname: page-component-7479d7b7d-767nl Total loading time: 0 Render date: 2024-07-13T14:34:08.696Z Has data issue: false hasContentIssue false

A combination of pirfenidone and TGF-β inhibition mitigates cystic echinococcosis-associated hepatic injury

Published online by Cambridge University Press:  15 February 2021

Erqiang Wang
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China Department of Hunan Children's Research Institute, Hunan Children's Hospital, Changsha, China
Zhenyu Liao
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
Lianghai Wang
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
Yuan Liao
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
Xiaodan Xu
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
Ping Liu
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
Xian Wang
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
Jun Hou
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
Huijiao Jiang
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
Xiangwei Wu*
Affiliation:
Department of Hepatobiliary Surgery, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
Xueling Chen*
Affiliation:
Department of Basic Medical Sciences, Shihezi University School of Medicine, Shihezi, Xinjiang, 832002, China
*
Author for correspondence: Xueling Chen, E-mail: chenxueling@shzu.edu.cn; Xiangwei Wu, E-mail: wxwshz@126.com
Author for correspondence: Xueling Chen, E-mail: chenxueling@shzu.edu.cn; Xiangwei Wu, E-mail: wxwshz@126.com

Abstract

Cystic echinococcosis (CE) occurs in the intermediate host's liver, assuming a bladder-like structure surrounded by the host-derived collagen capsule mainly derived from activated hepatic stellate cells (HSCs). However, the effect of CE on liver natural killer (NK) cells and the potential of transforming growth factor-β (TGF-β) signalling inhibition on alleviating CE-related liver damage remain to be explored. Here, by using the CE-mouse model, we revealed that the inhibitory receptors on the surface of liver NK cells were up-regulated, whereas the activating receptors were down-regulated over time. TGF-β1 secretion was elevated in liver tissues and mainly derived from macrophages. A combination of TGF-β signalling inhibitors SB525334 and pirfenidone could reduce the expression of TGF-β1 signalling pathway-related proteins and collagen production. Based on the secretion of TGF-β1, only the pirfenidone group showed a depressing effect. Also, the combination of SB525334 and pirfenidone exhibited a higher potential in effectively alleviating the senescence of the hepatocytes and restoring liver function. Together, TGF-β1 may be a potential target for the treatment of CE-associated liver fibrosis.

Type
Research Article
Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

*

These authors contributed equally to this work.

References

Albright, CD, Salganik, RI, Craciunescu, CN, Mar, MH and Zeisel, SH (2003) Mitochondrial and microsomal derived reactive oxygen species mediate apoptosis induced by transforming growth factor-beta1 in immortalized rat hepatocytes. Journal of Cellular Biochemistry 89, 254261.CrossRefGoogle ScholarPubMed
Amri, M, Aissa, SA, Belguendouz, H, Mezioug, D and Touil-Boukoffa, C (2007) In vitro antihydatic action of IFN-gamma is dependent on the nitric oxide pathway. Journal of Interferon and Cytokine Research 27, 781787.CrossRefGoogle ScholarPubMed
Andre, P, Denis, C, Soulas, C, Bourbon-Caillet, C, Lopez, J, Arnoux, T, Blery, M, Bonnafous, C, Gauthier, L, Morel, A, Rossi, B, Remark, R, Breso, V, Bonnet, E, Habif, G, Guia, S, Lalanne, AI, Hoffmann, C, Lantz, O, Fayette, J, Boyer-Chammard, A, Zerbib, R, Dodion, P, Ghadially, H, Jure-Kunkel, M, Morel, Y, Herbst, R, Narni-Mancinelli, E, Cohen, RB and Vivier, E (2018) Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 17311743.e1713.10.1016/j.cell.2018.10.014CrossRefGoogle Scholar
Anton, OM, Peterson, ME, Hollander, MJ, Dorward, DW, Arora, G, Traba, J, Rajagopalan, S, Snapp, EL, Garcia, KC, Waldmann, TA and Long, EO (2020) Trans-endocytosis of intact IL-15Rα-IL-15 complex from presenting cells into NK cells favors signaling for proliferation. Proceedings of the National Academy of Sciences of the USA 117, 522531.CrossRefGoogle ScholarPubMed
Atmaca, HT, Gazyagci, AN, Terzi, OS and Sumer, T (2019) Role of stellate cells in hepatic echinococcosis in cattle. Journal of Parasitic Diseases: Official Organ of the Indian Society for Parasitology 43, 576582.CrossRefGoogle ScholarPubMed
Beschin, A, De Baetselier, P and Van Ginderachter, JA (2013) Contribution of myeloid cell subsets to liver fibrosis in parasite infection. The Journal of Pathology 229, 186197.CrossRefGoogle ScholarPubMed
Bird, TG, Müller, M, Boulter, L, Vincent, DF, Ridgway, RA, Lopez-Guadamillas, E, Lu, WY, Jamieson, T, Govaere, O, Campbell, AD, Ferreira-Gonzalez, S, Cole, AM, Hay, T, Simpson, KJ, Clark, W, Hedley, A, Clarke, M, Gentaz, P, Nixon, C, Bryce, S, Kiourtis, C, Sprangers, J, Nibbs, RJB, Van Rooijen, N, Bartholin, L, McGreal, SR, Apte, U, Barry, ST, Iredale, JP, Clarke, AR, Serrano, M, Roskams, TA, Sansom, OJ and Forbes, SJ (2018) TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Science Translational Medicine 10, eaan 1230. doi: 10.1126/scitranslmed.aan1230.CrossRefGoogle ScholarPubMed
Bonnans, C, Chou, J and Werb, Z (2014) Remodelling the extracellular matrix in development and disease. Nature Reviews Molecular Cell Biology 15, 786801.CrossRefGoogle ScholarPubMed
Cheng, YQ, Ren, JP, Zhao, J, Wang, JM, Zhou, Y, Li, GY, Moorman, JP and Yao, ZQ (2015) MicroRNA-155 regulates interferon-gamma production in natural killer cells Via Tim-3 signalling in chronic hepatitis C virus infection. Immunology 145, 485497.CrossRefGoogle ScholarPubMed
Cordero-Espinoza, L and Huch, M (2018) The balancing act of the liver: tissue regeneration versus fibrosis. The Journal of Clinical Investigation 128, 8596.CrossRefGoogle ScholarPubMed
Dewidar, B, Meyer, C, Dooley, S and Meindl-Beinker, AN (2019) TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells 8, 1419. doi: 10.3390/cells8111419.CrossRefGoogle ScholarPubMed
Distler, JHW, Gyorfi, AH, Ramanujam, M, Whitfield, ML, Konigshoff, M and Lafyatis, R (2019) Shared and distinct mechanisms of fibrosis. Nature Reviews Rheumatology 15, 705730.10.1038/s41584-019-0322-7CrossRefGoogle ScholarPubMed
Fasbender, F, Widera, A, Hengstler, JG and Watzl, C (2016) Natural killer cells and liver fibrosis. Frontiers in Immunology 7, 19.CrossRefGoogle ScholarPubMed
Flores-Contreras, L, Sandoval-Rodriguez, AS, Mena-Enriquez, MG, Lucano-Landeros, S, Arellano-Olivera, I, Alvarez-Alvarez, A, Sanchez-Parada, MG and Armendariz-Borunda, J (2014) Treatment with pirfenidone for two years decreases fibrosis, cytokine levels and enhances CB2 gene expression in patients with chronic hepatitis C. BMC Gastroenterology 14, 131.CrossRefGoogle ScholarPubMed
Gandhi, CR (2017) Hepatic stellate cell activation and pro-fibrogenic signals. Journal of Hepatology 67, 11041105.CrossRefGoogle ScholarPubMed
Guo, M (2017) Cellular senescence and liver disease: mechanisms and therapeutic strategies. Biomedicine & Pharmacotherapy 96, 15271537.CrossRefGoogle ScholarPubMed
Hata, A and Chen, YG (2016) TGF-β signaling from receptors to Smads. Cold Spring Harbor Perspectives in Biology 8, a022061-a022061. doi: 10.1101/cshperspect.a022061.CrossRefGoogle ScholarPubMed
He, S and Sharpless, NE (2017) Senescence in health and disease. Cell 169, 10001011.CrossRefGoogle ScholarPubMed
Hernandez-Segura, A, Nehme, J and Demaria, M (2018) Hallmarks of cellular senescence. Trends in Cell Biology 28, 436453.CrossRefGoogle ScholarPubMed
Heymann, F and Tacke, F (2016) Immunology in the liver – from homeostasis to disease. Nature Reviews. Gastroenterology & Hepatology 13, 88110.CrossRefGoogle ScholarPubMed
Jiao, J, Ooka, K, Fey, H, Fiel, MI, Rahmman, AH, Kojima, K, Hoshida, Y, Chen, X, de Paula, T, Vetter, D, Sastre, D, Lee, KH, Lee, Y, Bansal, M, Friedman, SL, Merad, M and Aloman, C (2016) Interleukin-15 receptor alpha on hepatic stellate cells regulates hepatic fibrogenesis in mice. Journal of Hepatology 65, 344353.CrossRefGoogle ScholarPubMed
Kisseleva, T and Brenner, D (2020) Molecular and cellular mechanisms of liver fibrosis and its regression. Nature Reviews. Gastroenterology & Hepatology 18, 151166. doi: 10.1038/s41575-020-00372-7.CrossRefGoogle ScholarPubMed
Kubes, P and Jenne, C (2018) Immune responses in the liver. Annual Review of Immunology 36, 247277.10.1146/annurev-immunol-051116-052415CrossRefGoogle ScholarPubMed
Lembarki, G and El Benna, N (2018) Echinococcal cysts in the liver. New England Journal of Medicine 379, 181.CrossRefGoogle ScholarPubMed
Li, YH, Zhou, WH, Tao, Y, Wang, SC, Jiang, YL, Zhang, D, Piao, HL, Fu, Q, Li, DJ and Du, MR (2016) The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal-fetal interface in early pregnancy. Cellular & Molecular Immunology 13, 7381.10.1038/cmi.2014.126CrossRefGoogle ScholarPubMed
Liu, Y, Abudounnasier, G, Zhang, T, Liu, X, Wang, Q, Yan, Y, Ding, J, Wen, H, Yimiti, D and Ma, X (2016) Increased expression of TGF-beta1 in correlation with liver fibrosis during Echinococcus granulosus infection in mice. Korean Journal of Parasitology 54, 519525.CrossRefGoogle ScholarPubMed
Long, EO, Kim, HS, Liu, D, Peterson, ME and Rajagopalan, S (2013) Controlling natural killer cell responses: integration of signals for activation and inhibition. Annual Review of Immunology 31, 227258.CrossRefGoogle Scholar
Lopez-de la Mora, DA, Sanchez-Roque, C, Montoya-Buelna, M, Sanchez-Enriquez, S, Lucano-Landeros, S, Macias-Barragan, J and Armendariz-Borunda, J (2015) Role and new insights of pirfenidone in fibrotic diseases. International Journal of Medical Sciences 12, 840847.CrossRefGoogle ScholarPubMed
Martinet, L and Smyth, MJ (2015) Balancing natural killer cell activation through paired receptors. Nature Reviews Immunology 15, 243254.CrossRefGoogle ScholarPubMed
Ndhlovu, LC, Lopez-Vergès, S, Barbour, JD, Jones, RB, Jha, AR, Long, BR, Schoeffler, EC, Fujita, T, Nixon, DF and Lanier, LL (2012) Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 119, 37343743.CrossRefGoogle ScholarPubMed
Pareek, A, Godavarthi, A, Issarani, R and Nagori, BP (2013) Antioxidant and hepatoprotective activity of Fagonia schweinfurthii (Hadidi) Hadidi extract in carbon tetrachloride induced hepatotoxicity in HepG2 cell line and rats. Journal of Ethnopharmacology 150, 973981.CrossRefGoogle ScholarPubMed
Peng, H, Wisse, E and Tian, Z (2016) Liver natural killer cells: subsets and roles in liver immunity. Cellular & Molecular Immunology 13, 328336.CrossRefGoogle ScholarPubMed
Roeb, E (2018) Matrix metalloproteinases and liver fibrosis (translational aspects). Matrix Biology 68–69, 463473.CrossRefGoogle Scholar
Schrader, J, Fallowfield, J and Iredale, JP (2009) Senescence of activated stellate cells: not just early retirement. Hepatology 49, 10451047.CrossRefGoogle ScholarPubMed
Seniutkin, O, Furuya, S, Luo, YS, Cichocki, JA, Fukushima, H, Kato, Y, Sugimoto, H, Matsumoto, T, Uehara, T and Rusyn, I (2018) Effects of pirfenidone in acute and sub-chronic liver fibrosis, and an initiation-promotion cancer model in the mouse. Toxicology and Applied Pharmacology 339, 19.10.1016/j.taap.2017.11.024CrossRefGoogle Scholar
Tamarozzi, F, Mariconti, M, Neumayr, A and Brunetti, E (2016) The intermediate host immune response in cystic echinococcosis. Parasite Immunology 38, 170181.CrossRefGoogle ScholarPubMed
Tominaga, K and Suzuki, HI (2019) TGF-β signaling in cellular senescence and aging-related pathology. International journal of molecular sciences 20, 5002. doi: 10.3390/ijms20205002.CrossRefGoogle ScholarPubMed
Tsochatzis, EA, Bosch, J and Burroughs, AK (2014) Liver cirrhosis. Lancet (London, England) 383, 17491761.CrossRefGoogle ScholarPubMed
Tsuchida, T and Friedman, SL (2017) Mechanisms of hepatic stellate cell activation. Nature Reviews. Gastroenterology & Hepatology 14, 397411.CrossRefGoogle ScholarPubMed
Viel, S, Marcais, A, Guimaraes, FS, Loftus, R, Rabilloud, J, Grau, M, Degouve, S, Djebali, S, Sanlaville, A, Charrier, E, Bienvenu, J, Marie, JC, Caux, C, Marvel, J, Town, L, Huntington, ND, Bartholin, L, Finlay, D, Smyth, MJ and Walzer, T (2016) TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway. Science Signaling 9, ra19.CrossRefGoogle ScholarPubMed
Wen, H, Vuitton, L, Tuxun, T, Li, J, Vuitton, DA, Zhang, W and McManus, DP (2019) Echinococcosis: advances in the 21st century. Clinical Microbiology Reviews 32, e00075-18. doi: 10.1128/cmr.00075-18.CrossRefGoogle ScholarPubMed
Zhang, K, Han, X, Zhang, Z, Zheng, L, Hu, Z, Yao, Q, Cui, H, Shu, G, Si, M, Li, C, Shi, Z, Chen, T, Han, Y, Chang, Y, Yao, Z, Han, T and Hong, W (2017) The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFbeta and Notch pathways. Nature Communications 8, 144.10.1038/s41467-017-00204-4CrossRefGoogle ScholarPubMed
Zheng, M, Sun, H and Tian, Z (2018) Natural killer cells in liver diseases. Frontiers of Medicine 12, 269279.CrossRefGoogle ScholarPubMed
Zhou, J, Peng, H, Li, K, Qu, K, Wang, B, Wu, Y, Ye, L, Dong, Z, Wei, H, Sun, R and Tian, Z (2019) Liver-resident NK cells control antiviral activity of hepatic T cells Via the PD-1-PD-L1 axis. Immunity 50, 403417.e404.CrossRefGoogle ScholarPubMed
Supplementary material: File

Wang et al. supplementary material

Figures S1-S3

Download Wang et al. supplementary material(File)
File 2.4 MB