Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/28935
Title: RIPK1-RIPK3-MLKL-Associated Necroptosis Drives Leishmania infantum Killing in Neutrophils
Authors: Barbosa, Laiana Arlego
Fiuza, Paloma Peixoto dos Santos
Borges, Letícia J
Rolim, Fellipe A
Andrade, Mayara B
Luz, Nivea Farias
Carvalho, Graziele Quintela de
Lima, Jonilson Berlink
Almeida, Roque Pacheco de
Chan, Francis K
Bozza, Marcelo Torres
Borges, Valeria de Matos
Prates, Deboraci Brito
Affilliation: Universidade Federal da Bahia. Salvador, BA, Brasil
Universidade Federal da Bahia. Salvador, BA, Brasil
Universidade Federal da Bahia. Salvador, BA, Brasil
Universidade Federal da Bahia. Salvador, BA, Brasil
Universidade Federal da Bahia. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Inflamação e Biomarcadores. Salvador, BA, Brasil
Universidade Federal da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Inflamação e Biomarcadores. Salvador, BA, Brasil / Instituto Federal de Educação, Ciência e Tecnologia Baiano. Santa Inês, BA, Brasil
Universidade do Oeste da Bahia. Centro de Ciências Biológicas e da Saúde. Barreiras, BA, Brasil
Universidade Federal de Sergipe. Departamento de Medicina. Aracaju, SE, Brasil
University of Massachusetts Medical School. Department of Pathology, Immunology and Microbiology Program. Worcester, MA, United States
Universidade Federal do Rio de Janeiro. Departamento de Imunologia. Rio de Janeiro, RJ, Brasil
Universidade Federal da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Inflamação e Biomarcadores. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Inflamação e Biomarcadores. Salvador, BA, Brasil / Universidade Federal da Bahia. Instituto de Ciências da Saúde. Departamento de Biomorfologia. Salvador, BA, Brasil
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 neutrophils displayed loss of membrane integrity, higher levels of ROS, and decreased L. infantum viability. Pharmacological inhibition of RIPK1 or RIPK3 increased parasite survival when caspase-8 was blocked. Electron microscopy assays revealed morphological features associated with necroptotic death in L. infantum infected-neutrophils pretreated with caspase inhibitor, whereas infected cells pretreated with RIPK1 and RIPK3 inhibitors did not show ultra-structural alterations in membrane integrity and presented viable Leishmania within parasitophorous vacuoles. Taken together, these findings suggest that inhibition of caspase-8 contributes to elimination of L. infantum in neutrophils by triggering necroptosis. Thus, targeting necroptosis may represent a new strategy to control Leishmania replication.
Keywords: Leishmania infantum
Neutrophils
Necroptosis
Cell death
RIPK3
Mixed lineage kinase domain-like
Caspase-8
keywords: Leishmania infantum
Neutrófilos
Necroptose
Morte celular
RIPK3
Linhagem mista parecida com domínio quinase
Caspase-8
Issue Date: 2018
Publisher: Frontiers Media
Citation: BARBOSA, L. A. et al. RIPK1-RIPK3-MLKL-Associated Necroptosis Drives Leishmania infantum Killing in Neutrophils. Frontiers in Immunology, v. 9, 1918.
DOI: 10.3389/fimmu.2018.01818
ISSN: 1664-3224
Copyright: open access
Appears in Collections:BA - IGM - Artigos de Periódicos

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