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Antileishmanial Drugs Modulate IL-12 Expression and Inflammasome Activation in Primary Human Cells

Sonia André, Vasco Rodrigues, Sarah Pemberton, Mireille Laforge, Yasmina Fortier, Anabela Cordeiro-da-Silva, Jane MacDougall and Jérôme Estaquier
J Immunol April 1, 2020, 204 (7) 1869-1880; DOI: https://doi.org/10.4049/jimmunol.1900590
Sonia André
*INSERM-U1124, Paris University, 75006 Paris, France;
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Vasco Rodrigues
*INSERM-U1124, Paris University, 75006 Paris, France;
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Sarah Pemberton
*INSERM-U1124, Paris University, 75006 Paris, France;
†Photeomix, 93160 Noisy Le Grand, France;
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Mireille Laforge
*INSERM-U1124, Paris University, 75006 Paris, France;
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  • ORCID record for Mireille Laforge
Yasmina Fortier
*INSERM-U1124, Paris University, 75006 Paris, France;
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Anabela Cordeiro-da-Silva
‡i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
§Instituto de Biologia Molecular e Celular da Universidade do Porto, 450-313 Porto, Portugal;
¶Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, 450-313 Porto, Portugal; and
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Jane MacDougall
†Photeomix, 93160 Noisy Le Grand, France;
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Jérôme Estaquier
*INSERM-U1124, Paris University, 75006 Paris, France;
‖Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, Quebec G1V 4G2, Canada
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Key Points

  • Antileishmanial drugs inhibit CD4 and CD8 T cell proliferation.

  • Antileishmanial drugs inhibit IL-12 expression in monocytes.

  • Amphotericin B induces NLRP3 inflammasome activation.

Abstract

Leishmaniases are neglected tropical diseases. The treatment of leishmaniasis relies exclusively on chemotherapy including amphotericin B (AmB), miltefosine (hexadecylphosphocholine), and pentamidine. Besides the fact that these molecules are harmful for patients, little is known about the impact of such antileishmanial drugs on primary human cells in relation to immune function. The present study demonstrates that all antileishmanial drugs inhibit CD4 and CD8 T cell proliferation at the doses that are not related to increased cell death. Our results highlight that antileishmanial drugs have an impact on monocytes by altering the expression of IL-12 induced by LPS, whereas only AmB induced IL-10 secretion; both cytokines are essential in regulating Th1 cell–mediated immunity. Interestingly, IL-12 and anti–IL-10 Abs improved T cell proliferation inhibited by AmB. Furthermore, our results show that in contrast to hexadecylphosphocholine and pentamidine, AmB induced gene expression of the inflammasome pathway. Thus, AmB induced IL-1β and IL-18 secretions, which are reduced by specific inhibitors of caspase activation (Q-VD) and NLRP3 activation (MCC950). Our results reveal previously underestimated effects of antileishmanial drugs on primary human cells.

Footnotes

  • This work was supported by the European Community’s Seventh Framework Programme under Grant 602773 (Project KINDRED). S.A. is supported by a postdoctoral fellowship granted by the Fédération de Recherche Médicale (SPF20160936115) and by Infect-Era (FP7; Project INLEISH). V.R. is supported by a postdoctoral fellowship granted by KINDRED. J.E. is supported by the Canada Research Chair program.

  • Abbreviations used in this article:

    AmB
    amphotericin B
    ASC
    apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain
    CL
    cutaneous leishmaniasis
    ct
    threshold cycle
    DiOC6
    3,3′-dihexyloxacarbocyanine iodide
    HePC
    hexadecylphosphocholine
    Δψm
    mitochondrial membrane potential
    PI
    propidium iodide
    PS
    phosphatidylserine
    qPCR
    quantitative PCR
    VL
    visceral leishmaniasis.

  • Received May 23, 2019.
  • Accepted February 2, 2020.
  • Copyright © 2020 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 204 (7)
The Journal of Immunology
Vol. 204, Issue 7
1 Apr 2020
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Antileishmanial Drugs Modulate IL-12 Expression and Inflammasome Activation in Primary Human Cells
Sonia André, Vasco Rodrigues, Sarah Pemberton, Mireille Laforge, Yasmina Fortier, Anabela Cordeiro-da-Silva, Jane MacDougall, Jérôme Estaquier
The Journal of Immunology April 1, 2020, 204 (7) 1869-1880; DOI: 10.4049/jimmunol.1900590

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Antileishmanial Drugs Modulate IL-12 Expression and Inflammasome Activation in Primary Human Cells
Sonia André, Vasco Rodrigues, Sarah Pemberton, Mireille Laforge, Yasmina Fortier, Anabela Cordeiro-da-Silva, Jane MacDougall, Jérôme Estaquier
The Journal of Immunology April 1, 2020, 204 (7) 1869-1880; DOI: 10.4049/jimmunol.1900590
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