An association of Aquaporin-4 with the immunoregulation of liver pathology in mice infected with Schistosoma japonicum

Particle and Fibre Toxicology

Chuan Su²  Feng Liu²  Yingying Qian³  Wei Li²  Sha Zhou²  Xiaoxiao Dong²  Yong Li²  Xiaowei Yang²  Xiaojun Chen²  Xue Xue¹  Zhipeng Xu²  Xian Song²  Jifeng Zhu²  Weiwei Zhang² 

[1] Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China;Department of Pathogen Biology & Immunology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu, China;Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu, China

关键词: Treg cells;    Th17;    Th2;    Th1;    Granuloma;    Schistosoma japonicum;    Aquaporin-4;   

Others  :  1147585
DOI  :  10.1186/s13071-015-0650-7

 received in 2014-04-19, accepted in 2015-01-10,  发布年份 2015

【 摘 要 】

Background

Schistosomiasis is a chronic parasitic disease that affects approximately 200 million people. In Schistosomiasis japonica and mansoni, parasite eggs were trapped in host liver and stimulated the CD4⁺T cell responses to regulate the formation of the granulomas. Subsequently, excessive granulomatous response in some heavily, and/or repeatedly infected individuals could result in chronic liver fibrosis and circulatory impairment. Thus, elucidation of the mechanisms of these responses will not only provide more information to better understand the mechanisms of the immunoregulation in schistosomiasis, but also help to design new therapies to control granuloma-associated immunopathology. The role of aquaporin-4 (AQP4) in water transport has been extensively investigated in the central nervous system (CNS). Recently, studies have shown that AQP4 expresses in immune system and lack of AQP4 in mice results in significantly less CD4⁺CD25⁺ T regulatory cells (Treg cells) under physiological condition, one of the subpopulations of CD4⁺T cells which restrains immunopathology in hosts with schistosomiasis. However, little information exists regarding the contribution of AQP4 to the immune regulation in schistosome infection.

Methods

The liver granulomatous response in S. japonicum-infected AQP4 knockout (KO) mice and its wild-type (WT) littermates were detected by staining liver sections with hematoxylin and eosin. The generation of various CD4⁺ T subsets, including Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry. In addition, the levels of total IgG, IgG1, IgG2a in serum of infected mice were detected by ELISA assay.

Results

Our results showed an enhanced granulomatous response with increased accumulation of eosinophils and macrophages around eggs in the liver of AQP4 KO mice with Schistosomiasis japonica. In addition, our study demonstrated enhanced Th2 but reduced Th1 and Treg cells generation in AQP4 KO mice with Schistosomiasis japonica, which may, at least partly, account for the enhancement of the liver granuloma formation.

Conclusion

Our study for the first time provides evidences that AQP4 has an association with the immunoregulation of the liver granuloma formation, which may confer a new option for schistosomiasis treatment.

【 授权许可】

   
2015 Zhang et al.; licensee BioMed central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. Lancet. 2006; 368:1106-18.
• [2]Li XX, Zhou XN. Co-infection of tuberculosis and parasitic diseases in humans: a systematic review. Parasit Vectors. 2013; 6:79. BioMed Central Full Text
• [3]Pearce EJ, MacDonald AS. The immunobiology of schistosomiasis. Nat Rev Immunol. 2002; 2:499-511.
• [4]Wilson MS, Mentink-Kane MM, Pesce JT, Ramalingam TR, Thompson R, Wynn TA. Immunopathology of schistosomiasis. Immunol Cell Biol. 2007; 85:148-54.
• [5]Hams E, Aviello G, Fallon PG. The schistosoma granuloma: friend or foe? Front Immunol. 2013; 4:89.
• [6]Zhu D, He X, Duan Y, Chen J, Wang J, Sun X et al.. Expression of microRNA-454 in TGF-beta1-stimulated hepatic stellate cells and in mouse livers infected with Schistosoma japonicum. Parasit Vectors. 2014; 7:148. BioMed Central Full Text
• [7]Tallima H, Salah M, Guirguis FR, El Ridi R. Transforming growth factor-beta and Th17 responses in resistance to primary murine schistosomiasis mansoni. Cytokine. 2009; 48:239-45.
• [8]Wynn TA, Thompson RW, Cheever AW, Mentink-Kane MM. Immunopathogenesis of schistosomiasis. Immunol Rev. 2004; 201:156-67.
• [9]Wen X, He L, Chi Y, Zhou S, Hoellwarth J, Zhang C et al.. Dynamics of Th17 cells and their role in Schistosoma japonicum infection in C57BL/6 mice. PLoS Negl Trop Dis. 2011; 5:e1399.
• [10]Li J, Zhuang W, Cong L, Shi W, Cai X, Huang F et al.. Cyclophilin A from Schistosoma japonicum promotes a Th2 response in mice. Parasit Vectors. 2013; 6:330. BioMed Central Full Text
• [11]Hirata M, Kage M, Hara T, Yoneda Y, Zhang M, Fukuma T. Schistosoma japonicum egg granuloma formation in the interleukin-4 or interferon-gamma deficient host. Parasite Immunol. 2001; 23:271-80.
• [12]Singh KP, Gerard HC, Hudson AP, Reddy TR, Boros DL. Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice. Immunology. 2005; 114:410-7.
• [13]Baumgart M, Tompkins F, Leng J, Hesse M. Naturally occurring CD4 + Foxp3+ regulatory T cells are an essential, IL-10-independent part of the immunoregulatory network in Schistosoma mansoni egg-induced inflammation. J Immunol. 2006; 176:5374-87.
• [14]Kaplan MH, Whitfield JR, Boros DL, Grusby MJ. Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. J Immunol. 1998; 160:1850-6.
• [15]Rutitzky LI, Stadecker MJ. Exacerbated egg-induced immunopathology in murine Schistosoma mansoni infection is primarily mediated by IL-17 and restrained by IFN-gamma. Eur J Immunol. 2011; 41:2677-87.
• [16]Turner JD, Jenkins GR, Hogg KG, Aynsley SA, Paveley RA, Cook PC et al.. CD4 + CD25+ regulatory cells contribute to the regulation of colonic Th2 granulomatous pathology caused by schistosome infection. PLoS Negl Trop Dis. 2011; 5:e1269.
• [17]Xu YH, Macedonia J, Sher A, Pearce E, Cheever AW. Dynamic analysis of splenic Th1 and Th2 lymphocyte functions in mice infected with Schistosoma japonicum. Infect Immun. 1991; 59:2934-40.
• [18]Zhang Y, Chen L, Gao W, Hou X, Gu Y, Gui L et al.. IL-17 neutralization significantly ameliorates hepatic granulomatous inflammation and liver damage in Schistosoma japonicum infected mice. Eur J Immunol. 2012; 42:1523-35.
• [19]Hasegawa H, Ma T, Skach W, Matthay MA, Verkman AS. Molecular cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues. J Biol Chem. 1994; 269:5497-500.
• [20]Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW et al.. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000; 6:159-63.
• [21]Papadopoulos MC, Verkman AS. Aquaporin water channels in the nervous system. Nat Rev Neurosci. 2013; 14:265-77.
• [22]Venero JL, Vizuete ML, Ilundain AA, Machado A, Echevarria M, Cano J. Detailed localization of aquaporin-4 messenger RNA in the CNS: preferential expression in periventricular organs. Neuroscience. 1999; 94:239-50.
• [23]Varrin-Doyer M, Spencer CM, Schulze-Topphoff U, Nelson PA, Stroud RM, Cree BA et al.. Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann Neurol. 2012; 72:53-64.
• [24]Chan KH, Zhang R, Kwan JS, Guo VY, Ho PW, Ho JW et al.. Aquaporin-4 autoantibodies cause asymptomatic aquaporin-4 loss and activate astrocytes in mouse. J Neuroimmunol. 2012; 245:32-8.
• [25]Jarius S, Wildemann B. Aquaporin-4 antibodies, CNS acidosis and neuromyelitis optica: A potential link. Med Hypotheses. 2013; 81:1090-5.
• [26]Chi Y, Fan Y, He L, Liu W, Wen X, Zhou S et al.. Novel role of aquaporin-4 in CD4+ CD25+ T regulatory cell development and severity of Parkinson's disease. Aging Cell. 2011; 10:368-82.
• [27]Fan Y, Zhang J, Sun XL, Gao L, Zeng XN, Ding JH et al.. Sex- and region-specific alterations of basal amino acid and monoamine metabolism in the brain of aquaporin-4 knockout mice. J Neurosci Res. 2005; 82:458-64.
• [28]Rutitzky LI, Hernandez HJ, Stadecker MJ. Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection. Proc Natl Acad Sci U S A. 2001; 98:13243-8.
• [29]Cheng YL, Song WJ, Liu WQ, Lei JH, Mo HM, Ruppel A et al.. The effects of T cell deficiency on the development of worms and granuloma formation in mice infected with Schistosoma japonicum. Parasitol Res. 2008; 102:1129-34.
• [30]Burke ML, McManus DP, Ramm GA, Duke M, Li Y, Jones MK et al.. Temporal expression of chemokines dictates the hepatic inflammatory infiltrate in a murine model of schistosomiasis. PLoS Negl Trop Dis. 2010; 4:e598.
• [31]Metwali A, Elliott D, Mathew R, Blum A, Weinstock JV. IL-2 contributes to the IL-5 response in granulomas from mice infected with Schistosoma mansoni. J Immunol. 1993; 150:536-42.
• [32]Kelada S, Sethupathy P, Okoye IS, Kistasis E, Czieso S, White SD et al.. miR-182 and miR-10a are key regulators of Treg specialisation and stability during Schistosome and Leishmania-associated inflammation. PLoS Pathog. 2013; 9:e1003451.
• [33]de Almeida AB, Silva MC, Braga C, Freedman DO. Differences in the frequency of cytokine-producing cells in antigenemic and nonantigenemic individuals with bancroftian filariasis. Infect Immun. 1998; 66:1377-83.
• [34]Dieli F, Ivanyi J, Marsh P, Williams A, Naylor I, Sireci G et al.. Characterization of lung gamma delta T cells following intranasal infection with Mycobacterium bovis bacillus Calmette-Guerin. J Immunol. 2003; 170:463-9.
• [35]Ismaili J, van der Sande M, Holland MJ, Sambou I, Keita S, Allsopp C et al.. Plasmodium falciparum infection of the placenta affects newborn immune responses. Clin Exp Immunol. 2003; 133:414-21.
• [36]Li YS, Ross AG, Sleigh AC, Li Y, Waine GJ, Williams GJ et al.. Antibody isotype responses, infection and re-infection for Schistosoma japonicum in a marshland area of China. Acta Trop. 1999; 73:79-92.
• [37]Wynn TA, Cheever AW, Jankovic D, Poindexter RW, Caspar P, Lewis FA et al.. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature. 1995; 376:594-6.
• [38]Ashton PD, Harrop R, Shah B, Wilson RA. The schistosome egg: development and secretions. Parasitology. 2001; 122:329-38.
• [39]Mountford AP, Fisher A, Wilson RA. The profile of IgG1 and IgG2a antibody responses in mice exposed to Schistosoma mansoni. Parasite Immunol. 1994; 16:521-7.
• [40]Agre P. Nobel Lecture. Aquaporin water channels. Biosci Rep. 2004; 24:127-63.
• [41]Song MG, Hwang SY, Park JI, Yoon S, Bae HR, Kwak JY. Role of aquaporin 3 in development, subtypes and activation of dendritic cells. Mol Immunol. 2011; 49:28-37.