Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain

Autores
Arroyo, Daniela Soledad; Gaviglio, Emilia Andrea; Peralta Ramos, Javier María; Bussi, Claudio; Avalos, Maria Paula; Cancela, Liliana Marina; Iribarren, Pablo
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B+ CD45+ cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions.
Fil: Arroyo, Daniela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Gaviglio, Emilia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Peralta Ramos, Javier María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Bussi, Claudio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Avalos, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina
Fil: Cancela, Liliana Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina
Fil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Materia
AUTOPHAGY
INFLAMMATION
MYELOID CELLS
PEPTIDOGLYCAN
PHOSPHATIDYL-INOSITOL-3 KINASE INHIBITORS
TLR2
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/88714
Acceder
id CONICETDig_ec1dc4c11032bee1e74bdd1082116554
oai_identifier_str oai:ri.conicet.gov.ar:11336/88714
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brainArroyo, Daniela SoledadGaviglio, Emilia AndreaPeralta Ramos, Javier MaríaBussi, ClaudioAvalos, Maria PaulaCancela, Liliana MarinaIribarren, PabloAUTOPHAGYINFLAMMATIONMYELOID CELLSPEPTIDOGLYCANPHOSPHATIDYL-INOSITOL-3 KINASE INHIBITORSTLR2https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B+ CD45+ cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions.Fil: Arroyo, Daniela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gaviglio, Emilia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Peralta Ramos, Javier María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Bussi, Claudio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Avalos, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Cancela, Liliana Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFrontiers Media S.A.2018-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/88714Arroyo, Daniela Soledad; Gaviglio, Emilia Andrea; Peralta Ramos, Javier María; Bussi, Claudio; Avalos, Maria Paula; et al.; Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain; Frontiers Media S.A.; Frontiers in Immunology; 9; APR; 4-20181664-3224CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://journal.frontiersin.org/article/10.3389/fimmu.2018.00770/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2018.00770info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:06:45Zoai:ri.conicet.gov.ar:11336/88714instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 12:06:46.279CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain
title Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain
spellingShingle Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain
Arroyo, Daniela Soledad
AUTOPHAGY
INFLAMMATION
MYELOID CELLS
PEPTIDOGLYCAN
PHOSPHATIDYL-INOSITOL-3 KINASE INHIBITORS
TLR2
title_short Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain
title_full Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain
title_fullStr Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain
title_full_unstemmed Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain
title_sort Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain
dc.creator.none.fl_str_mv Arroyo, Daniela Soledad
Gaviglio, Emilia Andrea
Peralta Ramos, Javier María
Bussi, Claudio
Avalos, Maria Paula
Cancela, Liliana Marina
Iribarren, Pablo
author Arroyo, Daniela Soledad
author_facet Arroyo, Daniela Soledad
Gaviglio, Emilia Andrea
Peralta Ramos, Javier María
Bussi, Claudio
Avalos, Maria Paula
Cancela, Liliana Marina
Iribarren, Pablo
author_role author
author2 Gaviglio, Emilia Andrea
Peralta Ramos, Javier María
Bussi, Claudio
Avalos, Maria Paula
Cancela, Liliana Marina
Iribarren, Pablo
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv AUTOPHAGY
INFLAMMATION
MYELOID CELLS
PEPTIDOGLYCAN
PHOSPHATIDYL-INOSITOL-3 KINASE INHIBITORS
TLR2
topic AUTOPHAGY
INFLAMMATION
MYELOID CELLS
PEPTIDOGLYCAN
PHOSPHATIDYL-INOSITOL-3 KINASE INHIBITORS
TLR2
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B+ CD45+ cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions.
Fil: Arroyo, Daniela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Gaviglio, Emilia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Peralta Ramos, Javier María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Bussi, Claudio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Avalos, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina
Fil: Cancela, Liliana Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina
Fil: Iribarren, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
description Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl-inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B+ CD45+ cells and colocalization of LC3B and lysosomal-associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3-MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions.
publishDate 2018
dc.date.none.fl_str_mv 2018-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/88714
Arroyo, Daniela Soledad; Gaviglio, Emilia Andrea; Peralta Ramos, Javier María; Bussi, Claudio; Avalos, Maria Paula; et al.; Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain; Frontiers Media S.A.; Frontiers in Immunology; 9; APR; 4-2018
1664-3224
CONICET Digital
CONICET
url http://hdl.handle.net/11336/88714
identifier_str_mv Arroyo, Daniela Soledad; Gaviglio, Emilia Andrea; Peralta Ramos, Javier María; Bussi, Claudio; Avalos, Maria Paula; et al.; Phosphatidyl-Inositol-3 kinase inhibitors regulate peptidoglycan-induced myeloid leukocyte recruitment, inflammation, and neurotoxicity in mouse brain; Frontiers Media S.A.; Frontiers in Immunology; 9; APR; 4-2018
1664-3224
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://journal.frontiersin.org/article/10.3389/fimmu.2018.00770/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2018.00770
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media S.A.
publisher.none.fl_str_mv Frontiers Media S.A.
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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