Summary
Immunopathological mechanisms of schistosomiasis, a debilitating parasitic disease, are still unclear. In this study, we investigated the involvement of CX3C chemokine ligand 1 (CX3CL1) and its sole receptor CX3CR1 in the development of liver fibrosis in schistosomiasis. The animal model of schistosomiasis was established by infection of C57BL/6 mice with Schistosoma japonicum cercariae; mice injected with carbon tetrachloride (CCl4) were used as positive control of liver injury. After 4 and 8 weeks, the degree of liver lesions was assessed by hematoxylin and eosin staining, serum levels of hyaluronic acid (HA) were analyzed by a chemiluminescence immunoassay, liver fibrosis was evaluated by immunohistochemistry analysis of α-smooth muscle actin (α-SMA) expression, and CX3CL1 and CX3CR1 expression in the liver was measured by immunohistochemistry and real-time PCR. The results showed that at 8 weeks after Schistosoma infection, serum HA levels were increased and α-SMA-expressing cells appeared in the liver, indicating fibrogenesis. CX3CL1- and CX3CR1-positive cells were observed in the outer layer of granulomas formed around Schistosoma eggs in liver tissues, which was consistent with the significant upregulation of hepatic CX3CL1 and CX3CR1 mRNA expression at 4 and 8 weeks post-infection. Furthermore, correlation analysis revealed positive association between CX3CL1 and CX3CR1 expression and serum HA levels at 8 weeks post-infection, indicating a link between fibrogenesis and the CX3CL1/CX3CR1 axis in schistosomiasis. In conclusion, our data suggest the involvement of CX3CL1 and CX3CR1 in the progression of liver fibrosis caused by Schistosoma infection.
Similar content being viewed by others
References
Loverde PT. Schistosomiasis. Adv Exp Med Biol, 2019, 1154:45–70
Mcmanus DP, Dunne DW, Sacko M, et al. Schistosomiasis. Nat Rev Dis Primers, 2018,4(1): 13
El-Tonsy MM, Hussein HM, Helal Tel S, et al. Schistosoma mansoni infection: is it a risk factor for development of hepatocellular carcinoma?. Acta Trop, 2013,128(3): 542–547
Cook PC, Owen H, Deaton AM, et al. A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells. Nat Commun, 2015, 6: 6920
Ran L, Yu Q, Zhang S, et al. Cx3cr1 deficiency in mice attenuates hepatic granuloma formation during acute schistosomiasis by enhancing the M2-type polarization of macrophages. Dis Model Mech, 2015,8(7): 691–700
Hundhausen C, Misztela D, Berkhout TA, et al. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood, 2003,102(4): 1186–1195
Bonecchi R, Galliera E, Borroni EM, et al. Chemokines and chemokine receptors: an overview. Front Biosci (Landmark Ed), 2009,14:540–551
Shi Y, Zhang Z, Cai D, et al. Urokinase Attenuates Pulmonary Thromboembolism in an Animal Model by Inhibition of Inflammatory Response. J Immunol Res, 2018,2018:6941368
Roche SL, Wyse-Jackson AC, Ruiz-Lopez AM, et al. Fractalkine-CX3CR1 signaling is critical for progesterone-mediated neuroprotection in the retina. Sci Rep, 2017,7:43067
Sasaki M, Miyakoshi M, Sato Y, et al. Chemokine-chemokine receptor CCL2-CCR2 and CX3CL1-CX3CR1 axis may play a role in the aggravated inflammation in primary biliary cirrhosis. Dig Dis Sci, 2014,59(2): 358–364
Martinez-Hervas S, Vinue A, Nunez L, et al. Insulin resistance aggravates atherosclerosis by reducing vascular smooth muscle cell survival and increasing CX3CL1/CX3CR1 axis. Cardiovasc Res, 2014,103(2): 324–336
Zhuang Q, Ou J, Zhang S, et al. Crosstalk between the CX3CL1/CX3CR1 Axis and Inflammatory Signaling Pathways in Tissue Injury. Curr Protein Pept Sci, 2019,20(8): 844–854
Helmke A, Nordlohne J, Balzer MS, et al. CX3CL1-CX3CR1 interaction mediates macrophage-mesothelial cross talk and promotes peritoneal fibrosis. Kidney Int, 2019,95(6): 1405–1417
Aoyama T, Inokuchi S, Brenner DA, et al. CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology, 2010,52(4): 1390–1400
Liu P, Li J, Yang X, et al. Helminth infection inhibits airway allergic reaction and dendritic cells are involved in the modulation process. Parasite Immunol, 2010,32(1): 57–66
Zhou S, ** X, Li Y, et al. Blockade of PD-1 Signaling Enhances Th2 Cell Responses and Aggravates Liver Immunopathology in Mice with Schistosomiasis japonica. PLoS Negl Trop Dis, 2016,10(10): e0005094
Andrade ZA. Schistosomiasis and liver fibrosis. Parasite Immunol, 2009,31(11):656–663
Ishida Y, Kimura A, Nosaka M, et al. Essential involvement of the CX3CL1-CX3CR1 axis in bleomycin-induced pulmonary fibrosis via regulation of fibrocyte and M2 macrophage migration. Sci Rep, 2017, 7(1):16833
Efsen E, Grappone C, Defranco RM, et al. Up-regulated expression of fractalkine and its receptor CX3CR1 during liver injury in humans. J Hepatol, 2002,37(1): 39–47
Wasmuth HE, Zaldivar MM, Berres ML, et al. The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection. J Hepatol, 2008,48(2): 208–215
Isse K, Harada K, Zen Y, et al. Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts. Hepatology, 2005,41(3): 506–516
Li ZY, **ao L, Lin G, et al. Contribution of tissue transglutaminase to the severity of hepatic fibrosis resulting from Schistosoma japonicum infection through the regulation of IL-33/ST2 expression. Parasit Vectors, 2019,12(1): 302
Lu P, Li L, Kuno K, et al. Protective roles of the fractalkine/CX3CL1-CX3CR1 interactions in alkali-induced corneal neovascularization through enhanced antiangiogenic factor expression. J Immunol, 2008, 180(6):4283–4291
Rossi E, Adams LA, Bulsara M, et al. Assessing liver fibrosis with serum marker models. Clin Biochem Rev, 2007,28(1): 3–10
Ricard-Blum S, Hartmann DJ, Grenard P, et al. Relationships between several markers of extracellular matrix turn-over and ultrasonography in human Schistosomiasis mansoni. Am J Trop Med Hyg, 1999, 60(4):658–663
Marinho CC, Bretas T, Voieta I, et al. Serum hyaluronan and collagen IV as non-invasive markers of liver fibrosis in patients from an endemic area for schistosomiasis mansoni: a field-based study in Brazil. Mem Inst Oswaldo Cruz, 2010,105(4): 471–478
Karlmark KR, Zimmermann HW, Roderburg C, et al. The fractalkine receptor CX(3)CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology, 2010,52(5): 1769–1782
Author information
Authors and Affiliations
Corresponding author
Additional information
This study was supported by the National Key Technology Rearch & Development Program of China (No. 2015BAI09B06).
Conflict of Interest Statement
The authors declare that there are no conflicts of interest associated with this article.
Rights and permissions
About this article
Cite this article
Zhang, P., Wang, Bj., Wang, Jz. et al. Association of CX3CL1 and CX3CR1 Expression with Liver Fibrosis in a Mouse Model of Schistosomiasis. CURR MED SCI 40, 1121–1127 (2020). https://doi.org/10.1007/s11596-020-2294-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11596-020-2294-x