RIPK1-RIPK3-MLKL-Associated Necroptosis Drives Leishmania infantum Killing in Neutrophils

Frontiers in Immunology
Laiana A BarbosaDeboraci B Prates

Abstract

Necroptosis is a pro-inflammatory cell death, which happens in the context of caspase-8 inhibition, allowing activation of the receptor interacting protein kinase 1-receptor interacting protein kinase 3-mixed lineage kinase domain-like (RIPK1-RIPK3-MLKL) axis. Recently, necroptosis has emerged as a key component of resistance against pathogens including infected macrophage by Leishmania infantum, the ethiologic agent of Visceral leishmaniasis (VL). VL is the most severe form of Leishmaniasis, characterized by systemic inflammation and neutropenia. However, the role of neutrophil cell death in VL has not been characterized. Here, we showed that VL patients exhibited increased lactate dehydrogenase levels in the serum, a hallmark of cell death and tissue damage. We investigated the effect of necroptosis in neutrophil infection in vitro. Human neutrophils pretreated with zVAD-fmk (pan-caspase inhibitor) and zIETD-fmk (caspase-8 inhibitor) increased reactive oxygen species (ROS) level in response to Leishmania infection, which is associated with necroptotic cell death. MLKL, an important effector molecule downstream of necroptosis pathway, was also required for Leishmania killing. Moreover, in absence of caspases-8, murine neutroph...Continue Reading

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Aug 23, 2020·Cell Death & Disease·Mark A Miles, Christine J Hawkins
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Feb 20, 2021·Apoptosis : an International Journal on Programmed Cell Death·Jing ZhangWei Ding
Jul 3, 2021·International Journal of Molecular Sciences·Christine J Hawkins, Mark A Miles

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Methods Mentioned

BETA
RIP
flow cytometry
lavage
ELISA

Software Mentioned

GraphPad
GraphPad Prism
CellQuest
ImageQuant

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