Author | Barbosa, Laiana Arlego | |
Author | Fiuza, Paloma Peixoto dos Santos | |
Author | Borges, Letícia J | |
Author | Rolim, Fellipe A | |
Author | Andrade, Mayara B | |
Author | Luz, Nivea Farias | |
Author | Carvalho, Graziele Quintela de | |
Author | Lima, Jonilson Berlink | |
Author | Almeida, Roque Pacheco de | |
Author | Chan, Francis K | |
Author | Bozza, Marcelo Torres | |
Author | Borges, Valeria de Matos | |
Author | Prates, Deboraci Brito | |
Access date | 2018-09-20T14:02:59Z | |
Available date | 2018-09-20T14:02:59Z | |
Document date | 2018 | |
Citation | BARBOSA, L. A. et al. RIPK1-RIPK3-MLKL-Associated Necroptosis Drives Leishmania infantum Killing in Neutrophils. Frontiers in Immunology, v. 9, 1918. | pt_BR |
ISSN | 1664-3224 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/28935 | |
Sponsorship | Fundação de Amparo
à Pesquisa do Estado da Bahia-FAPESB (JCB0047/2013 to DP,
5760/2015 to VB) and from Conselho Nacional de Desenvolvimento
Científico e Tecnológico-CNPq (482722/2013-4 to DP,
552721/2011-5 and 019.203.02712/2009-8 FAPITEC/CNPq to
RA). RA also received a grant from Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior (CAPES: 23038.
005304/2011-01). NFL received funding from CAPES (grants
88887.142000/2017-00 and 88887.137958/2017-00). FC is supported
by NIH grant AI119030. LAB and LJB received a fellowship
from CNPq | pt_BR |
Language | eng | pt_BR |
Publisher | Frontiers Media | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | Leishmania infantum | pt_BR |
Subject in Portuguese | Neutrófilos | pt_BR |
Subject in Portuguese | Necroptose | pt_BR |
Subject in Portuguese | Morte celular | pt_BR |
Subject in Portuguese | RIPK3 | pt_BR |
Subject in Portuguese | Linhagem mista parecida com domínio quinase | pt_BR |
Subject in Portuguese | Caspase-8 | pt_BR |
Title | RIPK1-RIPK3-MLKL-Associated Necroptosis Drives Leishmania infantum Killing in Neutrophils | pt_BR |
Type | Article | pt_BR |
DOI | 10.3389/fimmu.2018.01818 | |
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. | pt_BR |
Affilliation | Universidade Federal da Bahia. Salvador, BA, Brasil | pt_BR |
Affilliation | Universidade Federal da Bahia. Salvador, BA, Brasil | pt_BR |
Affilliation | Universidade Federal da Bahia. Salvador, BA, Brasil | pt_BR |
Affilliation | Universidade Federal da Bahia. Salvador, BA, Brasil | pt_BR |
Affilliation | Universidade Federal da Bahia. Salvador, BA, Brasil | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Inflamação e Biomarcadores. Salvador, BA, Brasil | pt_BR |
Affilliation | 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 | pt_BR |
Affilliation | Universidade do Oeste da Bahia. Centro de Ciências Biológicas e da Saúde. Barreiras, BA, Brasil | pt_BR |
Affilliation | Universidade Federal de Sergipe. Departamento de Medicina. Aracaju, SE, Brasil | pt_BR |
Affilliation | University of Massachusetts Medical School. Department of Pathology, Immunology and Microbiology Program. Worcester, MA, United States | pt_BR |
Affilliation | Universidade Federal do Rio de Janeiro. Departamento de Imunologia. Rio de Janeiro, RJ, Brasil | pt_BR |
Affilliation | Universidade Federal da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Laboratório de Inflamação e Biomarcadores. Salvador, BA, Brasil | pt_BR |
Affilliation | 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 | pt_BR |
Subject | Leishmania infantum | pt_BR |
Subject | Neutrophils | pt_BR |
Subject | Necroptosis | pt_BR |
Subject | Cell death | pt_BR |
Subject | RIPK3 | pt_BR |
Subject | Mixed lineage kinase domain-like | pt_BR |
Subject | Caspase-8 | pt_BR |