Hostname: page-component-76fb5796d-dfsvx Total loading time: 0 Render date: 2024-04-26T08:24:08.695Z Has data issue: false hasContentIssue false
  • English
  • Français

Dog hepatocytes are key effector cells in the liver innate immune response to Leishmania infantum

Published online by Cambridge University Press:  18 December 2018

A. Rodrigues ,
G. Alexandre-Pires ,
A. Valério-Bolas ,
D. Santos-Mateus ,
M. Rafael-Fernandes ,
M. A. Pereira ,
D. Ligeiro ,
T. Nunes ,
R. Alves-Azevedo  and
S. Lopes-Ventura
...Show all authors
A. Rodrigues
Affiliation:
Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
G. Alexandre-Pires
Affiliation:
CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade Técnica, 1300-477 Lisbon, Portugal
A. Valério-Bolas
Affiliation:
Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
D. Santos-Mateus
Affiliation:
Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
M. Rafael-Fernandes
Affiliation:
Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
M. A. Pereira
Affiliation:
Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
D. Ligeiro
Affiliation:
IPST-Centro de Sangue e Transplantação de Lisboa, Alameda das Linhas de Torres 117, 1749-005 Lisbon, Portugal
T. Nunes
Affiliation:
Microscopy Center, Faculty of Sciences, Campo Grande, 1749-016 Lisboa, Portugal
R. Alves-Azevedo
Affiliation:
Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
S. Lopes-Ventura
Affiliation:
Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
M. Santos
Affiliation:
CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade Técnica, 1300-477 Lisbon, Portugal
A. M. Tomás
Affiliation:
I3S, Instituto de Investigação e Inovação em Saúde, IBMC, Instituto de Biologia Molecular e Celular and, Instituto de Ciências Biomédicas Abel Salazar, ICBAS Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
I. Pereira da Fonseca
Affiliation:
CIISA, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Av. Universidade Técnica, 1300-477 Lisbon, Portugal
G. Santos-Gomes*
Affiliation:
Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade Nova de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
*
Author for correspondence: Gabriela M. Santos-Gomes, E-mail: santosgomes@ihmt.unl.pt
Get access Rights & Permissions [Opens in a new window]

Abstract

Hepatocytes constitute the majority of hepatic cells, and play a key role in controlling systemic innate immunity, via pattern-recognition receptors (PRRs) and by synthesizing complement and acute phase proteins. Leishmania infantum, a protozoan parasite that causes human and canine leishmaniasis, infects liver by establishing inside the Kupffer cells. The current study proposes the elucidation of the immune response generated by dog hepatocytes when exposed to L. infantum. Additionally, the impact of adding leishmanicidal compound, meglumine antimoniate (MgA), to parasite-exposed hepatocytes was also addressed. L. infantum presents a high tropism to hepatocytes, establishing strong membrane interactions. The possibility of L. infantum internalization by hepatocytes was raised, but not confirmed. Hepatocytes were able to recognize parasite presence, inducing PRRs [nucleotide oligomerization domain (NOD)1, NOD2 and Toll-like receptor (TLR)2] gene expression and generating a mix pro- and anti-inflammatory cytokine response. Reduction of cytochrome P 450s enzyme activity was also observed concomitant with the inflammatory response. Addition of MgA increased NOD2, TLR4 and interleukin 10 gene expression, indicating an immunomodulatory role for MgA. Hepatocytes seem to have a major role in coordinating liver's innate immune response against L. infantum infection, activating inflammatory mechanisms, but always balancing the inflammatory response in order to avoid cell damage.

Keywords

Hepatocytesinnate immunityLeishmania infantummeglumine antimoniate
Type
Research Article
Information
Parasitology , Volume 146 , Issue 6 , May 2019 , pp. 753 - 764
Check for updates
Copyright
Copyright © Cambridge University Press 2018 

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.)

References

Alexandre-Pires, G, de Brito, MT, Algueró, C, Martins, C, Rodrigues, OR, Pereira da Fonseca, I and Santos-Gomes, G (2010) Canine leishmaniosis. Immunophenotypic profile of leukocytes in different compartments of symptomatic, asymptomatic and treated dogs. Veterinary Immunology and Immunopathology 137, 275–283.Google Scholar
Ato, M, Maroof, A, Zubairi, S, Nakano, H, Kakiuchi, T and Kaye, PM (2006) Loss of dendritic cell migration and impaired resistance to Leishmania donovani infection in mice deficient in CCL19 and CCL21. Journal of Immunology 176, 5486–5493.Google Scholar
Bankoti, R and Stäger, S (2012) Differential regulation of the immune response in the spleen and liver of mice infected with Leishmania donovani. Journal of Tropical Medicine 2012, 639304.Google Scholar
Becker, I, Salaiza, N, Aguirre, M, Delgado, J, Carrillo-Carrasco, N, Kobeh, LG, Ruiz, A, Cervantes, R, Torres, AP, Cabrera, N, González, A, Maldonado, C and Isibasi, A (2003) Leishmania lipophosphoglycan (LPG) activates NK cells through toll-like receptor-2. Molecular and Biochemical Parasitology 130, 65–74.Google Scholar
Bigorgne, AE and Crispe, IN (2010) TLRs in hepatic cellular crosstalk. Gastroenterology Research and Practice 2010, 1–7.Google Scholar
Blumberg, RS, Koss, T, Story, CM, Barisani, D, Polischuk, J, Lipin, A, Pablo, L, Green, R and Simister, NE (1995) A major histocompatibility complex class I-related Fc receptor for IgG on rat hepatocytes. The Journal of Clinical Investigation 95, 2397–2402.Google Scholar
Broering, R, Lu, M and Schlaak, JF (2011) Role of toll-like receptors in liver health and disease. Clinical Science 121, 415–426.Google Scholar
Dini, L, Pagliara, P and Carlà, EC (2002) Phagocytosis of apoptotic cells by liver: a morphological study. Microscopy Research and Technique 57, 530–540.Google Scholar
Duarte, MIS, Mariano, ON and Corbett, CEP (1989) Liver parenchymal cell parasitism in human visceral leishmaniasis. Virchows Archiv: A Pathological Anatomy and Histopathology 415, 1–6.Google Scholar
Franchi, L, Warner, N, Viani, K and Nuñez, G (2009) Function of NOD-like receptors in microbial recognition and host defense. Immunological Reviews 227, 106–128.Google Scholar
Gangneux, JP, Lemenand, O, Reinhard, Y, Guiguen, C, Guguen-Guillouzo, C and Gripon, P (2005) In vitro and ex vivo permissivity of hepatocytes for Leishmania donovani. Journal of Eukaryotic Microbiology 52, 489–491.Google Scholar
Gao, B, Jeong, WI and Tian, Z (2007) Liver: an organ with predominant innate immunity. Hepatology 47, 729–736.Google Scholar
Gruys, E, Toussaint, MJM, Niewold, TA and Koopmans, SJ (2005) Acute phase reaction and acute phase proteins. Journal of Zhejiang University Science B 6, 1045–1056.Google Scholar
Gupta, G, Oghumu, S and Satoskar, AR (2013) Mechanisms of immune evasion in leishmaniasis. Advances in Applied Microbiology 82, 155–184.Google Scholar
Heinrich, PC, Behrmann, I, Muller-Newen, G, Schaper, F and Graeve, L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway 1. Biochemical Journal 334, 297–314.Google Scholar
Inohara, N and Nuñez, G (2001) The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene 20, 6473–6481.Google Scholar
Jenne, CN and Kubes, P (2013) Immune surveillance by the liver. Nature Immunology 14, 996–1006.Google Scholar
Johansson, S, Forsberg, E and Lundgren, B (1987) Comparison of fibronectin receptors from rat hepatocytes and fibroblasts. The Journal of Biological Chemistry 262, 7819–7824.Google Scholar
Jura, J and Koj, A (2011) Regulatory mechanisms controlling inflammation and synthesis of acute phase proteins. In Veas, F (ed.), Acute Phase Proteins – Regulation and Functions of Acute Phase Proteins. London, UK: IntechOpen Limited, pp. 61–84. ISBN: 978-953-307-252-4.Google Scholar
Kaye, PM and Beattie, L (2016) Lessons from other diseases: granulomatous inflammation in leishmaniasis. Seminars in Immunopathology 38, 249–260.Google Scholar
Mahmoud, AE, Attia, RA, Eldeek, HE, Farrag, HMM and Makboul, R (2016) Polymerase chain reaction detection and inducible nitric-oxide synthase expression of Leishmania major in mice inoculated by two different routes. Tropical Parasitology 6, 42–50.Google Scholar
Marques, CS, Passero, LFD, Vale-Gato, I, Rodrigues, A, Rodrigues, OR, Martins, C, Correia, I, Tomás, AM, Alexandre-Pires, G, Ferronha, MH and Santos-Gomes, GM (2015) New insights into neutrophil and Leishmania infantum in vitro immune interactions. Comparative Immunology, Microbiology and Infectious Diseases 40, 19–29.Google Scholar
Melo, FA, Moura, EP, Ribeiro, RR, Alves, CF, Caliari, MV, Tafuri, WL, da Calabrese, KS and Tafuri, WL (2009) Hepatic extracellular matrix alterations in dogs naturally infected with Leishmania (leishmania) chagasi. International Journal of Experimental Pathology 90, 538–548.Google Scholar
Miranda, JP, Leite, SB, Muller-Vieira, U, Rodrigues, A, Carrondo, MJT and Alves, PM (2009) Towards an extended functional hepatocyte in vitro culture. Tissue Engineering Part C: Methods 15, 157–167.Google Scholar
Miranda, JP, Rodrigues, A, Tostões, RM, Leite, S, Zimmerman, H, Carrondo, MJT and Alves, PM (2010) Extending hepatocyte functionality for drug-testing applications using high-viscosity alginate-encapsulated three-dimensional cultures in bioreactors. Tissue Engineering Part C: Methods 16, 1223–1232.Google Scholar
Mitra, V and Metcalf, J (2009) Metabolic functions of the liver. Anaesthesia & Intensive Care Medicine 10, 334–335.Google Scholar
Morgan, ET (2009) Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clinical Pharmacology and Therapeutics 85, 434–438.Google Scholar
Murray, HW (2008) Tissue granuloma structure-function in experimental visceral leishmaniasis. International Journal of Experimental Pathology 82, 249–267.Google Scholar
Murray, HW and Nathan, CF (1999) Macrophage microbicidal mechanisms in vivo: reactive nitrogen versus oxygen intermediates in the killing of intracellular visceral Leishmania donovani. The Journal of Experimental Medicine 189, 741–746.Google Scholar
Murray, HW, Tsai, CW, Liu, J and Ma, X (2006) Responses to Leishmania donovani in mice deficient in interleukin-12 (IL-12), IL-12/IL-23, or IL-18. Infection and Immunity 74, 4370–4374.Google Scholar
Olivier, M, Gregory, DJ and Forget, G (2005) Subversion mechanisms by which Leishmania parasites can escape the host immune response: a signaling point of view. Clinical Microbiology Reviews 18, 293–305.Google Scholar
Rodrigues, OR, Moura, RA, Gomes-Pereira, S and Santos-Gomes, GM (2006) H-2 complex influences cytokine gene expression in Leishmania infantum-infected macrophages. Cellular Immunology 243, 118–126.Google Scholar
Rodrigues, A, Santos-Mateus, D, Alexandre-Pires, G, Valério-Bolas, A, Rafael-Fernandes, M, Pereira, MA, Ligeiro, D, de Jesus, J, Alves-Azevedo, R, Lopes-Ventura, S, Santos, M, Tomás, AM, Pereira da Fonseca, I and Santos-Gomes, G (2017) Leishmania infantum exerts immunomodulation in canine Kupffer cells reverted by meglumine antimoniate. Comparative Immunology, Microbiology and Infectious Diseases 55, 42–52.Google Scholar
Rodríguez-Cortés, A, Carrillo, E, Martorell, S, Todolí, F, Ojeda, A, Martínez-Flórez, A, Urniza, A, Moreno, J and Alberola, J (2016) Compartmentalized immune response in leishmaniasis: changing patterns throughout the disease. PLoS ONE 11, 1–13.Google Scholar
Sanchez, MA, Diaz, NL, Zerpa, O, Negron, E, Convit, J and Tapia, FJ (2004) Organ-specific immunity in canine visceral leishmaniasis: analysis of symptomatic and asymptomatic dogs naturally infected with Leishmania chagasi. The American Journal of Tropical Medicine and Hygiene 70, 618–624.Google Scholar
Sant'Ana, JAP, Lima, WG, Oliveira, MR, Simões, LA, Michalick, MSM, Melo, MN, Tafuri, WL and Tafuri, WL (2007) Hepatic granulomas in canine visceral leishmaniasis and clinical status. Arquivo Brasileiro de Medicina Veterinária e Zootecnia 59, 1137–1144.Google Scholar
Santos-Gomes, GM and Abranches, P (1996) Comparative study of infectivity caused by promastigotes of Leishmania infantum MON-1, L. infantum MON-24 and L. donovani MON-18. Folia Parasitologica 43, 7–12.Google Scholar
Sarma, JV and Ward, PA (2011) The complement system. Cell and Tissue Research 343, 227–235.Google Scholar
Scott, MJ, Chen, C, Sun, Q and Billiar, TR (2010) Hepatocytes express functional NOD1 and NOD2 receptors: a role for NOD1 in hepatocyte CC and CXC chemokine production. Journal of Hepatology 53, 693–701.Google Scholar
Smelt, SC, Cotterell, SE, Engwerda, CR and Kaye, PM (2000) B cell-deficient mice are highly resistant to Leishmania donovani infection, but develop neutrophil-mediated tissue pathology. Journal of Immunology 164, 3681–3688.Google Scholar
Soji, T, Murata, Y, Ohira, A, Nishizono, H, Tanaka, M and Herbert, DC (1992) Evidence that hepatocytes can phagocytize exogenous substances. The Anatomical Record 233, 543–546.Google Scholar
Stanley, AC and Engwerda, CR (2007) Balancing immunity and pathology in visceral leishmaniasis. Immunology and Cell Biology 85, 138–147.Google Scholar
Streetz, KL, Wüstefeld, T, Klein, C, Manns, MP and Trautwein, C (2001) Mediators of inflammation and acute phase response in the liver. Cellular and Molecular Biology 47, 661–673.Google Scholar
Szabo, G, Dolganiuc, A and Mandrekar, P (2006) Pattern recognition receptors: a contemporary view on liver diseases. Hepatology 44, 287–298.Google Scholar
Ueno, N and Wilson, ME (2012) Receptor-mediated phagocytosis of Leishmania: implications for intracellular survival. Trends in Parasitology 28, 335–344.Google Scholar
Zhou, Z, Xu, MJ and Gao, B (2016) Hepatocytes: a key cell type for innate immunity. Cellular & Molecular Immunology 13, 301–315.Google Scholar
Supplementary material: File

Rodrigues et al. supplementary material

Rodrigues et al. supplementary material 1

Download Rodrigues et al. supplementary material(File)
File 2.8 MB