<em>Ageratina adenophora</em> causes spleen toxicity by inducing oxidative stress and pyroptosis in mice

Wei Sun

Chaorong Zeng

Dong Yue

Shanshan Liu

Table S1; Figure S.1; Figure S.2:

Click here to view.^{(225K, docx)}

^{Key Laboratory of Animal Disease and Environmental Hazards of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, Chengdu, Sichuan 611130, People's Republic of China}

^{Tongren Polytechnic College, Bijiang District, Tongren, Guizhou 554300, People's Republic of China}

^{Affiliated Sichuan Provincial Rehabilitation Hospital of Chengdu University of TCM, Sichuan Bayi Rehabilitation Center, Chengdu, Sichuan 611135, People's Republic of China}

Author for correspondence: Yanchun Hu e-mail: moc.361@411nuhcyh

Contributed by ^{Those authors contributed equally to this work.}

Electronic supplementary material is available online at https://dx.doi.org/10.6084/m9.figshare.c.4570538.

Received 2019 Apr 3; Accepted 2019 Jun 25.

Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

Abstract

Ageratina adenophora is an invasive weed with potent toxicological effects on livestock. Oxidative stress and pyroptosis play a pivotal role in regulating animal or human health and disease. The object of this study was to determine the mechanism underlying splenic toxicity induced by A. adenophora in a mouse model. Ageratina adenophora significantly increased the levels of reactive oxygen species and malondialdehyde, but decreased the antioxidants like catalase, superoxide dismutase, glutathione and glutathione peroxidase. In addition, the activity of the antioxidant enzymes was also decreased upon A. adenophora treatment. The induction of the pyroptosis pathway was evaluated in terms of the expression levels of Nod-like receptor protein 3, nuclear factor-κB, caspase-1, gasdermin-D and interleukin-1β, all of which were significantly elevated by A. adenophora. These findings suggest that A. adenophora impairs spleen function in mice through oxidative stress damage and pyroptosis.

Keywords: Ageratina adenophora, oxidative stress, reactive oxygen species, Nod-like receptor protein 3, pyroptosis

Abstract

Click here to view.^{(627K, pdf)}

Acknowledgements

Many thanks to Jinping Zhang, Fan Liu and Haiyang Zhou for their help in animal experiments.

Acknowledgements

References

1. Sharma OP, Dawra RK, Kurade NP, Sharma PD. 1998 A review of the toxicosis and biological properties of the genus Eupatorium. Nat. Toxins6, 1–14. (10.1002/(SICI)1522-7189(199802)6:13.0.CO;2-E) [] [[PubMed][Google Scholar]
2. Sui ZM, Hai L, Jie Y, Guo MQ, Yong W, Ling Y. 2018 Effects of Eupatorium adenophorum compost on soil characteristics and yield and quality of grape. Acta Pratacult. Sin.27, 88–96. (10.11686/cyxb2017127) [[PubMed][Google Scholar]
3. Zheng G, Luo S, Li S, Hua J, Li W, Li S. 2018 Specialized metabolites from Ageratina adenophora and their inhibitory activities against pathogenic fungi. Phytochemistry148, 57–62. (10.1016/j.phytochem.2018.01.013) [] [[PubMed][Google Scholar]
4. O'Sullivan BM. 2010 Investigations into Crofton weed (Eupatorium adenophorum) toxicity in horses. Aust. Vet. J.55, 19–21. (10.1111/j.1751-0813.1979.tb09538.x) [] [[PubMed][Google Scholar]
5. Oelrichs PB, Calanasan CA, Macleod JK, Seawright AA, Ng JC. 2010 Isolation of a compound from Eupatorium adenophorum (Spreng.) [Ageratina adenophora (Spreng.)] causing hepatotoxicity in mice. Nat. Toxins3, 350–354. (10.1002/nt.2620030505) [] [[PubMed][Google Scholar]
6. Dong Q, Zhao BY, Qiang GU, Wang L, Yan LU, Shi ZC. 2011 Toxicity test of Eupatorium adenophorum spreng on mice. J. Northw. Univ.41, 469–472. [PubMed][Google Scholar]
7. Katoch R, Sharma OP, Dawra RK, Kurade NP. 2000 Hepatotoxicity of Eupatorium adenophorum to rats. Toxicon38, 309–314. (10.1016/S0041-0101(99)00151-8) [] [[PubMed][Google Scholar]
8. Kaushal V, Dawra RK, Sharma OP, Kurade NP. 2001 Biochemical alterations in the blood plasma of rats associated with hepatotoxicity induced by Eupatorium adenophorum. Vet. Res. Commun.25, 601–608. (10.1023/a:1017933418167) [] [[PubMed][Google Scholar]
9. Verma A, Yadava BPS, Sampath KT. 1987 Possible use of Spreng (Eupatorium adenophorum) in animal feeding. Indian J. Anim. Nutr.4, 189. [PubMed][Google Scholar]
10. He YJ, et al. 2016. Induction of apoptosis and autophagy via mitochondria- and PI3 K/Akt/mTOR-mediated pathways by E. adenophorum in hepatocytes of Saanen goat. Oncotarget7, 54 537–54 548. (10.18632/oncotarget.10402) ] [
11. He YJ, et al. 2015. E. adenophorum induces cell cycle arrest and apoptosis of splenocytes through the mitochondrial pathway and caspase activation in Saanen goats. Sci. Rep.5, 15967 (10.1038/srep15967) ] [
12. He YJ, et al. 2015. E. adenophorum induces cell cycle and apoptosis of renal cells through mitochondrial pathway and caspase activation in Saanen goat. PLoS ONE10, e0138504 (10.1371/journal.pone.0138504) ] [
13. Singh YD, Mukhopadhayay SK, Shah MAA, Ali MA, Tolenkhomba TC. 2012 Effects of Eupatorium adenophorum on antioxidant enzyme status in a mice model. Internat. J. Pharm. Pharmaceut. Sci.4, 436–439. [PubMed][Google Scholar]
14. Sun W, et al. 2018. Ageratina adenophora induces mice hepatotoxicity via ROS-NLRP3-mediated pyroptosis. Sci. Rep.8, 16032 (10.1038/s41598-018-34492-7) ] [
15. Lu Y, et al. 2017. Sodium fluoride causes oxidative stress and apoptosis in the mouse liver. Aging9, 1623–1639. (10.18632/aging.101257) ] [
16. Jabs T. 1999 Reactive oxygen intermediates as mediators of programmed cell death in plants and animals. Biochem. Pharmacol.57, 231–245. (10.1016/S0006-2952(98)00227-5) [] [[PubMed][Google Scholar]
17. Schieber M, Chandel NS. 2014 ROS function in redox signaling and oxidative stress. Curr. Biol.24, R453–R462. (10.1016/j.cub.2014.03.034) ] [[Google Scholar]
18. Espinosa DC, Miguel V, Mennerich D, Kietzmann T, Sánchez-Pérez P, Cadenas S, Lamas S. 2015 Antioxidant responses and cellular adjustments to oxidative stress. Redox Biol.6, 183–197. (10.1016/j.redox.2015.07.008) ] [[Google Scholar]
19. Ďuračková Z. 2010 Some current insights into oxidative stress. Physiol. Res.59, 459. [[PubMed][Google Scholar]
20. Qiu Z, et al. 2017. NLRP3 inflammasome activation-mediated pyroptosis aggravates myocardial ischemia/reperfusion injury in diabetic rats. Oxid. Med. Cell. Longe.2017, 1–17. (10.1155/2017/9743280) ] [
21. Cervantes J, Nagata T, Uchijima M, Shibata K, Koide Y. 2007 Intracytosolic Listeria monocytogenes induces cell death through caspase-1 activation in murine macrophages. Cell. Microbiol.10, 41–52. (10.1111/j.1462-5822.2007.01012.x) [] [[PubMed][Google Scholar]
22. Aglietti RA, Dueber EC. 2017 Recent insights into the molecular mechanisms underlying pyroptosis and Gasdermin family functions. Trends Immunol.38, 261–271. (10.1016/j.it.2017.01.003) [] [[PubMed][Google Scholar]
23. Davis BK, Wen H, Ting JP. 2011 The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol.29, 707–735. (10.1016/j.it.2017.01.003) ] [[Google Scholar]
24. Liu Z, Lu G, Xu Y, Dan L, Qian R, Song W, Chao S. 2017 Melatonin alleviates inflammasome-induced pyroptosis through inhibiting NF-κB/GSDMD signal in mice adipose tissue. J. Pineal Res.29, e12414 (10.1111/jpi.12414) [] [[PubMed][Google Scholar]
25. Jorgensen I, Rayamajhi M, Miao EA. 2017 Programmed cell death as a defence against infection. Nat. Rev. Immunol.17, 151–164. (10.1038/nri.2016.147) ] [[Google Scholar]
26. Rathinam VAK, Fitzgerald KA. 2016 Inflammasome complexes: emerging mechanisms and effector functions. Cell165, 792–800. (10.1016/j.cell.2016.03.046) ] [[Google Scholar]
27. Boucher D, Chan A, Ross C, Schroder K. 2018 Quantifying caspase-1 activity in murine macrophages. Methods Mol. Biol.1725, 163–176. (10.1007/978-1-4939-7568-6_14) [] [[PubMed][Google Scholar]
28. Bergsbaken T, Fink SL, Cookson BT. 2009 Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol.7, 99–109. (10.1038/nrmicro2070) ] [[Google Scholar]
29. Yun JJ, Pyo S. 1988 Pneumococcal protein PspA facilitates Streptococcus pneumoniae-induced pyroptosis. Exp. Brain Res.71, 450–454. (10.1007/BF00247507) [[PubMed][Google Scholar]
30. Wang Z, et al. 2018. Role of pyroptosis in normal cardiac response to calorie restriction and starvation. Biochem. Bioph. Res. Co.495, 1122–1128. (10.1016/j.bbrc.2017.11.144) [] [[PubMed]
31. Fu J, et al. 2018. Dosage-dependent effects of Eupatorium adenophorum on Saanen goat blood levels and the histopathology of several organs. Pratacult. Sci.35, 434–440. [PubMed]
32. Altamura M, Caradonna L, Amati L, Pellegrino NM, Urgesi G, Miniello S. 2001 Splenectomy and sepsis: the role of the spleen in the immune-mediated bacterial clearance. Immunopharm. Immunotoxicol.23, 153–161. (10.1081/iph-100103856) [] [[PubMed][Google Scholar]
33. Nolte MA, Hamann A, Kraal G, Mebius RE. 2010 The strict regulation of lymphocyte migration to splenic white pulp does not involve common homing receptors. Immunology106, 299–307. (10.1046/j.1365-2567.2002.01443.x) ] [[Google Scholar]
34. Ouyang CB, Liu XM, Yan DD, Yuan LI, Wang QX, Cao AC, Guo MX. 2016 Immunotoxicity assessment of cadinene sesquiterpenes from Eupatorium adenophorum in mice. J. Integr. Agr.15, 2319–2325. (10.1016/S2095-3119(16)61403-X) [[PubMed][Google Scholar]
35. Lu P, Sang W, Ma K. 2005 Progress and prospects in research of an exotic invasive species, Eupatorium adenophorum. Acta Phytoecol. Sin.29, 1029–1037. (10.17521/cjpe.2005.0128) [[PubMed][Google Scholar]
36. Fink SL, Cookson BT. 2005 Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun.73, 1907–1916. (10.1128/iai.73.4.1907-1916.2005) ] [[Google Scholar]
37. Chandra J, Keshavkant S. 2018 Desiccation-induced ROS accumulation and lipid catabolism in recalcitrant Madhuca latifolia seeds. Physiol. Mol. Biol. Plants24, 75–87. (10.1007/s12298-017-0487-y) ] [[Google Scholar]
38. Tsikas D. 2016 Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges. Anal. Biochem.524, 13–30. (10.1016/j.ab.2016.10.021) [] [[PubMed][Google Scholar]
39. Ray PD, Huang BW, Tsuji Y. 2012 Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signalling. Cell. Signal.24, 981–990. (10.1016/j.cellsig.2012.01.008.Reactive) ] [[Google Scholar]
40. Lee EK, Kim JA, Kim JS, Park SJ, Heo K, Yang KM, Son TG. 2013 Activation of de novo GSH synthesis pathway in mouse spleen after long term low-dose γ-ray irradiation. Free Radical Res.47, 89–94. (10.3109/10715762.2012.747678) [] [[PubMed][Google Scholar]
41. Zhao Q, Wang X, Chen A, Cheng X, Zhang G, Sun J, Zhao Y, Huang Y, Zhu Y. 2018 Rhein protects against cerebral ischemic-/reperfusion-induced oxidative stress and apoptosis in rats. Int. J. Mol. Med.41, 2802–2812. (10.3892/ijmm.2018.3488) ] [[Google Scholar]
42. Mebius RE, Kraal G. 2005 Structure and function of the spleen. Nat. Rev. Immunol.5, 606–616. (10.1038/nri1669) [] [[PubMed][Google Scholar]
43. Liu X, Lieberman J. 2017 A mechanistic understanding of pyroptosis: the fiery death triggered by invasive infection. Adv. Immunol.135, 81–117. (10.1016/bs.ai.2017.02.002) [] [[PubMed][Google Scholar]
44. Xu F, Ji Q, Zhang J, Huang W, Cao Z, Li Y. 2018 AlCl3 inhibits LPS-induced NLRP3 inflammasome activation and IL-1β production through suppressing NF-κB signaling pathway in murine peritoneal macrophages. Chemosphere209, 972–980. (10.1016/j.chemosphere.2018.06.171) [] [[PubMed][Google Scholar]
45. Nathan C. 2002 Points of control in inflammation. Nature420, 846–852. (10.1038/nature01320) [] [[PubMed][Google Scholar]
46. Okayama Y. 2005 Oxidative stress in allergic and inflammatory skin diseases. Curr. Drug Targets Inflamm. Allergy4, 517–519. (10.2174/1568010054526386) [] [[PubMed][Google Scholar]
47. He W, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J. 2015 Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Curr. Drug Targets Inflamm. Allergy25, 1285–1298. (10.1038/cr.2015.139) ] [[Google Scholar]
48. Sun W, Zeng CR, Yue D, Liu SS, Ren ZH, Zuo ZC, Deng JL, Peng GN, Hu YC. 2019 Data from: Ageratina adenophora causes spleen toxicity by inducing oxidative stress and pyroptosis in mice Dryad Digital Repository. (10.5061/dryad.gf2np70) [[PubMed]