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Echinococcus granulosus cyst fluid suppresses inflammatory responses by inhibiting TRAF6 signalling in macrophages

Published online by Cambridge University Press:  29 March 2021

Ke Lin ,
Di Zhou ,
Min Li ,
Jin Meng ,
Feiming He ,
Xiaofeng Yang ,
Dan Dong Open the ORCID record for Dan Dong [Opens in a new window] ,
Xian Wang ,
Xiangwei Wu  and
Xueling Chen Open the ORCID record for Xueling Chen [Opens in a new window]
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Ke Lin
Affiliation:
Department of Immunology, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
Di Zhou
Affiliation:
Medical Laboratory, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
Min Li
Affiliation:
Nursing School of Shihezi University, Shihezi, Xinjiang, China
Jin Meng
Affiliation:
Department of Immunology, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
Feiming He
Affiliation:
Department of Immunology, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
Xiaofeng Yang
Affiliation:
Department of Immunology, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
Dan Dong
Affiliation:
Department of Immunology, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
Xian Wang
Affiliation:
Department of Immunology, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
Xiangwei Wu
Affiliation:
Department of Hepatobiliary Surgery, the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
Xueling Chen*
Affiliation:
Department of Immunology, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
Jun Hou*
Affiliation:
Department of Immunology, Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
*
Authors for correspondence: Xueling Chen, E-mail: chenxueling@shzu.edu.cn; Jun Hou, E-mail: houjun229@163.com
Authors for correspondence: Xueling Chen, E-mail: chenxueling@shzu.edu.cn; Jun Hou, E-mail: houjun229@163.com
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Abstract

Echinococcus granulosus sensu lato has complex defence mechanisms that protect it from the anti-parasitic immune response for long periods. Echinococcus granulosus cyst fluid (EgCF) is involved in the immune escape. Nevertheless, whether and how EgCF modulates the inflammatory response in macrophages remains poorly understood. Here, real-time polymerase chain reaction and enzyme-linked immunosorbent assay revealed that EgCF could markedly attenuate the lipopolysaccharide (LPS)-induced production of pro-inflammatory factors including tumour necrosis factor-α, interleukin (IL)-12 and IL-6 but increase the expression of IL-10 at mRNA and protein levels in mouse peritoneal macrophages and RAW 264.7 cells. Mechanically, western blotting and immunofluorescence assay showed that EgCF abolished the activation of nuclear factor (NF)-κB p65, p38 mitogen-activated protein kinase (MAPK) and ERK1/2 signalling pathways by LPS stimulation in mouse macrophages. EgCF's anti-inflammatory role was at least partly contributed by promoting proteasomal degradation of the critical adaptor TRAF6. Moreover, the EgCF-promoted anti-inflammatory response and TRAF6 proteasomal degradation were conserved in human THP-1 macrophages. These findings collectively reveal a novel mechanism by which EgCF suppresses inflammatory responses by inhibiting TRAF6 and the downstream activation of NF-κB and MAPK signalling in both human and mouse macrophages, providing new insights into the molecular mechanisms underlying the E. granulosus-induced immune evasion.

Keywords

Cystic echinococcosisEgCFinflammationmacrophagesTRAF6

Information

Type
Research Article
Information
Parasitology , Volume 148 , Issue 7 , June 2021 , pp. 887 - 894
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Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

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Footnotes

*

These authors contributed equally to this study.

References

Ahn, CS, Han, X, Bae, YA, Ma, X, Kim, JT, Cai, H, Yang, HJ, Kang, I, Wang, H and Kong, Y (2015) Alteration of immunoproteome profile of Echinococcus granulosus hydatid fluid with progression of cystic echinococcosis. Parasites & Vectors 8, 10.CrossRefGoogle ScholarPubMed
BelhassenGarcía, M, Romeroalegria, A, Velascotirado, V, AlonsoSardón, M, Lopezbernus, A, Alvelasuarez, L, Del Villar, LP, Carpioperez, A, Galindoperez, I and Corderosanchez, M (2014) Study of hydatidosis-attributed mortality in endemic area. PLoS One 9, e91342.CrossRefGoogle Scholar
Browne, EP (2020) The role of toll-like receptors in retroviral infection. Microorganisms 8, 1787.CrossRefGoogle ScholarPubMed
Chen, S, Fuller, KK, Dunlap, JC and Loros, JJ (2020) A pro- and anti-inflammatory axis modulates the macrophage circadian clock. Frontiers in Immunology 11, 867.CrossRefGoogle ScholarPubMed
da Silva, AM (2010) Human echinococcosis: a neglected disease. Gastroenterology Research and Practice 2010, 583297.CrossRefGoogle ScholarPubMed
Diaz, A (2017) Immunology of cystic echinococcosis (hydatid disease). British Medical Bulletin 124, 121–133.Google Scholar
Faria, CP, Neves, BM, Lourenço, Á, Cruz, MT, Martins, JD, Silva, A, Pereira, S and Sousa, MDC (2020) Giardia lamblia decreases NF-κB p65(RelA) protein levels and modulates LPS-induced pro-inflammatory response in macrophages. Scientific Reports 10, 6234.CrossRefGoogle ScholarPubMed
Gao, Q, Wei, A, Chen, F, Chen, X, Ding, W, Ding, Z, Wu, Z, Du, R and Cao, W (2020) Enhancing PPARgamma by HDAC inhibition reduces foam cell formation and atherosclerosis in ApoE deficient mice. Pharmacological Research 160, 105059.CrossRefGoogle ScholarPubMed
Gottstein, B, Soboslay, P, Ortona, E, Wang, J, Siracusano, A and Vuitton, D (2017) Immunology of alveolar and cystic echinococcosis (AE and CE). Advances in Parasitology 96, 1–54.CrossRefGoogle Scholar
Hasturk, H, Kantarci, A and Van Dyke, TE (2012) Oral inflammatory diseases and systemic inflammation: role of the macrophage. Frontiers in Immunology 3, 118.CrossRefGoogle ScholarPubMed
He, C, Jiang, H, Song, W, Riezman, H, Tontonoz, P, Weston, TA, Guagliardo, P, Kim, PH, Jung, R, Heizer, P, Fong, LG and Young, SG (2020) Cultured macrophages transfer surplus cholesterol into adjacent cells in the absence of serum or high-density lipoproteins. Proceedings of the National Academy of Sciences of the United States of America 117, 10476–10483.CrossRefGoogle ScholarPubMed
Hou, J, Li, L, Dong, D, Wang, L, Wang, X, Yang, K, Xu, X, Chen, C, Wu, X and Chen, X (2020) Glycomolecules in Echinococcus granulosus cyst fluid inhibit TLR4-mediated inflammatory responses via c-Raf. Cellular & Molecular Immunology 17, 423–425.CrossRefGoogle ScholarPubMed
Hübner, MP, Manfras, BJ, Margos, MC, Eiffler, D, Hoffmann, WH, Schulz-Key, H, Kern, P and Soboslay, PT (2006) Echinococcus multilocularis metacestodes modulate cellular cytokine and chemokine release by peripheral blood mononuclear cells in alveolar echinococcosis patients. Clinical & Experimental Immunology 145, 243–251.CrossRefGoogle ScholarPubMed
Iwasaki, A and Medzhitov, R (2015) Control of adaptive immunity by the innate immune system. Nature Immunology 16, 343–353.CrossRefGoogle ScholarPubMed
Jakus, PB, Kalman, N, Antus, C, Radnai, B, Tucsek, Z, Gallyas, F Jr, Sumegi, B and Veres, B (2013) TRAF6 is functional in inhibition of TLR4-mediated NF-κB activation by resveratrol. Journal of Nutritional Biochemistry 24, 819–823.CrossRefGoogle ScholarPubMed
Li, J, Ju, Y, Wang, X, Zhang, Z, Li, J, Zhu, M and Zhao, W (2013) Analysis of the chemical components of hydatid fluid from Echinococcus granulosus. Revista da Sociedade Brasilra de Medicina Tropical 46, 605–610.Google Scholar
Lin, RY, Wang, JH, Lu, XM, Zhou, XT, Mantion, G, Wen, H, Vuitton, DA and Richert, L (2009) Components of the mitogen-activated protein kinase cascade are activated in hepatic cells by Echinococcus multilocularis metacestode. World Journal of Gastroenterology 15, 2116–2124.CrossRefGoogle ScholarPubMed
McManus, DP, Gray, DJ, Zhang, W and Yang, Y (2012) Diagnosis, treatment, and management of echinococcosis. BMJ: British Medical Journal 344, e3866.CrossRefGoogle ScholarPubMed
Mokhtari Amirmajdi, M, Sankian, M, Eftekharzadeh Mashhadi, I, Varasteh, A, Vahedi, F, Sadrizadeh, A and Spotin, A (2011) Apoptosis of human lymphocytes after exposure to hydatid fluid. Iranian Journal of Parasitology 6, 9–16.Google ScholarPubMed
Monteiro, KM, de Carvalho, MO, Zaha, A and Ferreira, HB (2010) Proteomic analysis of the Echinococcus granulosus metacestode during infection of its intermediate host. Proteomics 10, 1985–1999.CrossRefGoogle ScholarPubMed
OudniM'rad, M, M'rad, S, Ksia, A, Lamiri, R, Mekki, M, Nouri, A, Mezhoud, H and Babba, H (2015) First molecular evidence of the simultaneous human infection with two species of Echinococcus granulosus sensu lato: Echinococcus granulosus sensu stricto and Echinococcus canadensis. Parasitology Research 115, 1065–1069.CrossRefGoogle Scholar
Park, HH (2018) Structure of TRAF family: current understanding of receptor recognition. Frontiers in Immunology 9, 1999.CrossRefGoogle ScholarPubMed
Park, Y, Pang, K, Park, J, Hong, E, Lee, J, Ooshima, A, Kim, H, Cho, J, Han, Y, Lee, C, Song, Y, Park, K, Yang, K and Kim, S (2020) Destablilization of TRAF6 by DRAK1 suppresses tumor growth and metastasis in cervical cancer cells. Cancer Research 80, 2537–2549.CrossRefGoogle ScholarPubMed
Peri, F, Piazza, M, Calabrese, V, Damore, G and Cighetti, R (2010) Exploring the LPS/TLR4 signal pathway with small molecules. Biochemical Society Transactions 38, 1390.CrossRefGoogle ScholarPubMed
Rossol, M, Heine, H, Meusch, U, Quandt, D, Klein, C, Sweet, M and Hauschildt, S (2011) LPS-induced cytokine production in human monocytes and macrophages. Critical Reviews in Immunology 31, 379–446.CrossRefGoogle ScholarPubMed
Schmid, D, Gruber, M, Piskaty, C, Woehs, F, Renner, A, Nagy, Z, Kaltenboeck, A, Wasserscheid, T, Bazylko, A and Kiss, AK (2012) Inhibition of NF-κB-dependent cytokine and inducible nitric oxide synthesis by the macrocyclic ellagitannin oenothein B in TLR-stimulated RAW 264.7 macrophages. Journal of Natural Products 75, 870.CrossRefGoogle ScholarPubMed
Shao, S, Sun, X, Chen, Y, Zhan, B and Zhu, X (2019) Complement evasion: an effective strategy that parasites utilize to survive in the host. Frontiers in Microbiology 10, 532.CrossRefGoogle ScholarPubMed
Singh, BB, Dhand, NK, Ghatak, S and Gill, JPS (2014) Economic losses due to cystic echinococcosis in India: need for urgent action to control the disease. Preventive Veterinary Medicine 113, 1–12.CrossRefGoogle ScholarPubMed
Siracusano, A, Delunardo, F, Teggi, A and Ortona, E (2012) Host-parasite relationship in cystic echinococcosis: an evolving story. Clinical & Developmental Immunology 2012, 639362.CrossRefGoogle Scholar
Srivastav, S, Kar, S, Chande, A, Mukhopadhyaya, R and Das, P (2012) Leishmania donovani exploits host deubiquitinating enzyme A20, a negative regulator of TLR signalling, to subvert host immune response. Journal of immunology (Baltimore, MD.: 1950), 189, 924–934.CrossRefGoogle Scholar
Toumi, O, Noomen, F, Salem, R, Rabeh, H, Jabra, SB, Korbi, I, Bannani, S, Nasr, M, Zouari, K, Mondher, G and Hamdi, A (2017) Intraperitoneal rupture of hydatid cysts. European Journal of Trauma and Emergency Surgery 43, 387–391.CrossRefGoogle ScholarPubMed
Vidya, MK, Kumar, VG, Sejian, V, Bagath, M, Krishnan, G and Bhatta, R (2018) Toll-like receptors: significance, ligands, signalling pathways, and functions in mammals. International Reviews of Immunology 37, 20–36.CrossRefGoogle Scholar
Walsh, MC, Lee, J and Choi, Y (2015) Tumor necrosis factor receptor-associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunological Reviews 266, 72–92.CrossRefGoogle ScholarPubMed
Wang, Y, Wang, Q, Lv, S and Zhang, S (2015a) Different protein of Echinococcus granulosus stimulates dendritic induced immune response. Parasitology 142, 879–889.CrossRefGoogle Scholar
Wang, Y, Zhou, H, Shen, Y, Wang, Y, Wu, W, Liu, H, Yuan, Z, Xu, Y, Hu, Y and Cao, J (2015b) Impairment of dendritic cell function and induction of CD4(+)CD25(+)Foxp3(+) T cells by excretory-secretory products: a potential mechanism of immune evasion adopted by Echinococcus granulosus. BMC Immunology 16, 44.CrossRefGoogle Scholar
Wang, G, Hu, Z, Fu, Q, Song, X, Cui, Q, Jia, R, Zou, Y, He, C, Li, L and Yin, Z (2017) Resveratrol mitigates lipopolysaccharide-mediated acute inflammation in rats by inhibiting the TLR4/NF-κBp65/MAPKs signalling cascade. Scientific Reports 7, 45006.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Yanbao, X, Fu, Q, Wenji, P, Chang, S, Wahl, LM, Medvedev, AE and Jbc, M (2011) Endotoxin tolerance impairs IL-1 receptor-associated kinase (IRAK) 4 and TGF-β-activated kinase 1 activation, K63-linked polyubiquitination and assembly of IRAK1, TNF receptor-associated factor 6, and IκB kinase γ and increases A20 expression. Journal of Biological Chemistry 286, 7905–7916.Google Scholar
Yang, XD and Sun, SC (2015) Targeting signalling factors for degradation, an emerging mechanism for TRAF functions. Immunological Reviews 266, 56–71.CrossRefGoogle Scholar
Yang, J, Wu, J, Fu, Y, Yan, L, Li, Y, Guo, X, Zhang, Y, Wang, X, Shen, Y, Cho, WC and Zheng, Y (2021) Identification of different extracellular vesicles in the hydatid fluid of Echinococcus granulosus and immunomodulatory effects of 110 K EVs on sheep PBMCs. Frontiers in Immunology 12, 602717.CrossRefGoogle ScholarPubMed
Yin, S, Chen, X, Zhang, J, Xu, F, Hou, J, Wu, X and Chen, X (2014) Initial studies on the role of hydatid fluid in the immune evasion strategies of Echinococcus granulosus. Pakistan Journal of Zoology 46, 1711–1718.Google Scholar
You-Nian, XU, Liu, GL, Meng, C, Anesthesiology, DO and Hospital, U (2016) Highly effective extraction of mouse peritoneal macrophages by quick vibrating method. Chinese General Practice 19, 303–306.Google Scholar
Zeghir-Bouteldja, R, Polome, A, Bousbata, S and Touil-Boukoffa, C (2017) Comparative proteome profiling of hydatid fluid from Algerian patients reveals cyst location-related variation in Echinococcus granulosus. Acta Tropica 171, 199–206.CrossRefGoogle ScholarPubMed
Zhang, C, Wang, L, Ali, T, Li, L, Bi, X, Wang, J, Lu, G, Shao, Y, Vuitton, DA, Wen, H and Lin, R (2016) Hydatid cyst fluid promotes peri-cystic fibrosis in cystic echinococcosis by suppressing miR-19 expression. Parasites & Vectors 9, 278.CrossRefGoogle ScholarPubMed
Zhao, W, Wang, L, Zhang, M, Yuan, C and Gao, C (2012) E3 ubiquitin ligase tripartite motif 38 negatively regulates TLR-mediated immune responses by proteasomal degradation of TNF receptor-associated factor 6 in macrophages. The Journal of Immunology 188, 2567–2574.CrossRefGoogle ScholarPubMed
Zhou, L, Ma, Q, Shi, H and Huo, K (2010) NUMBL interacts with TRAF6 and promotes the degradation of TRAF6. Biochemical & Biophysical Research Communications 392, 409–414.CrossRefGoogle ScholarPubMed
Zhou, X, Wang, W, Cui, F, Shi, C, Ma, Y, Yu, Y, Zhao, W and Zhao, J (2019) Extracellular vesicles derived from Echinococcus granulosus hydatid cyst fluid from patients: isolation, characterization and evaluation of immunomodulatory functions on T cells. International Journal for Parasitology 49, 1029–1037.CrossRefGoogle ScholarPubMed