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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