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Invariant NKT Cells Drive Hepatic Cytokinic Microenvironment Favoring Efficient Granuloma Formation and Early Control of Leishmania donovani Infection

The development of inflammatory granulomas around infected Kupffer cells is necessary for hepatic parasite clearance during visceral leishmaniasis. Invariant NKT (iNKT) cells are predominant T cells in the mouse liver and can synthesize large quantities of IL-4 and IFN-γ, two cytokines involved in g...

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Autores principales: Robert-Gangneux, Florence, Drogoul, Anne-Sophie, Rostan, Octavie, Piquet-Pellorce, Claire, Cayon, Jérome, Lisbonne, Mariette, Herbelin, André, Gascan, Hugues, Guiguen, Claude, Samson, Michel, Gangneux, Jean-Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310876/
https://www.ncbi.nlm.nih.gov/pubmed/22457760
http://dx.doi.org/10.1371/journal.pone.0033413
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author Robert-Gangneux, Florence
Drogoul, Anne-Sophie
Rostan, Octavie
Piquet-Pellorce, Claire
Cayon, Jérome
Lisbonne, Mariette
Herbelin, André
Gascan, Hugues
Guiguen, Claude
Samson, Michel
Gangneux, Jean-Pierre
author_facet Robert-Gangneux, Florence
Drogoul, Anne-Sophie
Rostan, Octavie
Piquet-Pellorce, Claire
Cayon, Jérome
Lisbonne, Mariette
Herbelin, André
Gascan, Hugues
Guiguen, Claude
Samson, Michel
Gangneux, Jean-Pierre
author_sort Robert-Gangneux, Florence
collection PubMed
description The development of inflammatory granulomas around infected Kupffer cells is necessary for hepatic parasite clearance during visceral leishmaniasis. Invariant NKT (iNKT) cells are predominant T cells in the mouse liver and can synthesize large quantities of IL-4 and IFN-γ, two cytokines involved in granuloma formation. This study analyzed the role of iNKT cells in the hepatic immune response during Leishmania donovani infection, using a murine model of wild-type (WT) and iNKT cell-deficient (Jα18(-/-)) C57BL/6 mice sacrificed 15, 30 or 60 days post-infection. We recorded hepatic parasite loads, cytokine expression, and analyzed granulomatous response by immunohistochemistry and hepatic immune cell infiltration by flow cytometry. Whereas WT animals rapidly controlled the infection and developed an inflammatory response associated with a massive influx of iNKT cells observed by flow cytometry, Jα18(-/-) mice had significantly higher parasitic loads on all time points. This lack of control of parasite burden was associated with a delay in granuloma maturation (28.1% of large granulomas at day 60 versus 50.7% in WT). Cytokine transcriptome analysis showed that mRNA of 90/101 genes encoding chemokines, cytokines and their receptors, was underexpressed in Jα18(-/-) mice. Detection of IL-4 and TNF-α by ELISA in liver extracts was also significantly lower in Jα18(-/-) mice. Consistent with flow cytometry analysis, cytokinome profile in WT mice showed a bias of expression towards T cell-chemoattractant chemokines on D15, and displayed a switch towards expression of granulocytes and/or monocytes -chemoattractant chemokines on D60. In Jα18(-/-) mice, the significantly lower expression of CXCL5, MIP-2 and CCL2 mRNA was correlated with a defect in myeloperoxidase positive-cell attraction observed by immunohistochemistry and with a lower granulocyte and monocyte infiltration in the liver, as shown by flow cytometry. These data indicate that iNKT cells play a role in early and sustained pro-inflammatory cytokine response warranting efficient organization of hepatic granulomas and parasite clearance.
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spelling pubmed-33108762012-03-28 Invariant NKT Cells Drive Hepatic Cytokinic Microenvironment Favoring Efficient Granuloma Formation and Early Control of Leishmania donovani Infection Robert-Gangneux, Florence Drogoul, Anne-Sophie Rostan, Octavie Piquet-Pellorce, Claire Cayon, Jérome Lisbonne, Mariette Herbelin, André Gascan, Hugues Guiguen, Claude Samson, Michel Gangneux, Jean-Pierre PLoS One Research Article The development of inflammatory granulomas around infected Kupffer cells is necessary for hepatic parasite clearance during visceral leishmaniasis. Invariant NKT (iNKT) cells are predominant T cells in the mouse liver and can synthesize large quantities of IL-4 and IFN-γ, two cytokines involved in granuloma formation. This study analyzed the role of iNKT cells in the hepatic immune response during Leishmania donovani infection, using a murine model of wild-type (WT) and iNKT cell-deficient (Jα18(-/-)) C57BL/6 mice sacrificed 15, 30 or 60 days post-infection. We recorded hepatic parasite loads, cytokine expression, and analyzed granulomatous response by immunohistochemistry and hepatic immune cell infiltration by flow cytometry. Whereas WT animals rapidly controlled the infection and developed an inflammatory response associated with a massive influx of iNKT cells observed by flow cytometry, Jα18(-/-) mice had significantly higher parasitic loads on all time points. This lack of control of parasite burden was associated with a delay in granuloma maturation (28.1% of large granulomas at day 60 versus 50.7% in WT). Cytokine transcriptome analysis showed that mRNA of 90/101 genes encoding chemokines, cytokines and their receptors, was underexpressed in Jα18(-/-) mice. Detection of IL-4 and TNF-α by ELISA in liver extracts was also significantly lower in Jα18(-/-) mice. Consistent with flow cytometry analysis, cytokinome profile in WT mice showed a bias of expression towards T cell-chemoattractant chemokines on D15, and displayed a switch towards expression of granulocytes and/or monocytes -chemoattractant chemokines on D60. In Jα18(-/-) mice, the significantly lower expression of CXCL5, MIP-2 and CCL2 mRNA was correlated with a defect in myeloperoxidase positive-cell attraction observed by immunohistochemistry and with a lower granulocyte and monocyte infiltration in the liver, as shown by flow cytometry. These data indicate that iNKT cells play a role in early and sustained pro-inflammatory cytokine response warranting efficient organization of hepatic granulomas and parasite clearance. Public Library of Science 2012-03-22 /pmc/articles/PMC3310876/ /pubmed/22457760 http://dx.doi.org/10.1371/journal.pone.0033413 Text en Robert-Gangneux et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Robert-Gangneux, Florence
Drogoul, Anne-Sophie
Rostan, Octavie
Piquet-Pellorce, Claire
Cayon, Jérome
Lisbonne, Mariette
Herbelin, André
Gascan, Hugues
Guiguen, Claude
Samson, Michel
Gangneux, Jean-Pierre
Invariant NKT Cells Drive Hepatic Cytokinic Microenvironment Favoring Efficient Granuloma Formation and Early Control of Leishmania donovani Infection
title Invariant NKT Cells Drive Hepatic Cytokinic Microenvironment Favoring Efficient Granuloma Formation and Early Control of Leishmania donovani Infection
title_full Invariant NKT Cells Drive Hepatic Cytokinic Microenvironment Favoring Efficient Granuloma Formation and Early Control of Leishmania donovani Infection
title_fullStr Invariant NKT Cells Drive Hepatic Cytokinic Microenvironment Favoring Efficient Granuloma Formation and Early Control of Leishmania donovani Infection
title_full_unstemmed Invariant NKT Cells Drive Hepatic Cytokinic Microenvironment Favoring Efficient Granuloma Formation and Early Control of Leishmania donovani Infection
title_short Invariant NKT Cells Drive Hepatic Cytokinic Microenvironment Favoring Efficient Granuloma Formation and Early Control of Leishmania donovani Infection
title_sort invariant nkt cells drive hepatic cytokinic microenvironment favoring efficient granuloma formation and early control of leishmania donovani infection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310876/
https://www.ncbi.nlm.nih.gov/pubmed/22457760
http://dx.doi.org/10.1371/journal.pone.0033413
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