Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses
Microglial cells are recognized as very dynamic brain cells, screening the environment and sensitive to signals from all other cell types in health and disease. Apolipoprotein D (ApoD), a lipid-binding protein of the Lipocalin family, is required for nervous system optimal function and proper develo...
| Autores: | , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Salamanca (USAL) |
| Repositorio: | GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| OAI Identifier: | oai:gredos.usal.es:10366/154862 |
| Acceso en línea: | http://hdl.handle.net/10366/154862 |
| Access Level: | acceso abierto |
| Palabra clave: | acute response amyloid-beta endocytosis astrocyte-microglia crosstalk cytokine secretion immune memory membrane-binding protein microglia myelin phagocytosis Phagocytosis Immunologic Memory Microglia 6310.03 Enfermedad medicina |
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Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responsesCorraliza-Gomez, MiriamBendito, BeatrizSandonis-Camarero, DavidMondejar-Duran, JorgeVilla, MiguelPoncela, MartaValero, JorgeSánchez, DiegoGanfornina, Maria Doloresacute responseamyloid-beta endocytosisastrocyte-microglia crosstalkcytokine secretionimmune memorymembrane-binding proteinmicrogliamyelin phagocytosisamyloid-beta endocytosisPhagocytosisImmunologic MemoryMicroglia6310.03 EnfermedadmedicinaMicroglial cells are recognized as very dynamic brain cells, screening the environment and sensitive to signals from all other cell types in health and disease. Apolipoprotein D (ApoD), a lipid-binding protein of the Lipocalin family, is required for nervous system optimal function and proper development and maintenance of key neural structures. ApoD has a cell and state-dependent expression in the healthy nervous system, and increases its expression upon aging, damage or neurodegeneration. An extensive overlap exists between processes where ApoD is involved and those where microglia have an active role. However, no study has analyzed the role of ApoD in microglial responses. In this work, we test the hypothesis that ApoD, as an extracellular signal, participates in the intercellular crosstalk sensed by microglia and impacts their responses upon physiological aging or damaging conditions. We find that a significant proportion of ApoD-dependent aging transcriptome are microglia-specific genes, and show that lack of ApoD in vivo dysregulates microglial density in mouse hippocampus in an age-dependent manner. Murine BV2 and primary microglia do not express ApoD, but it can be internalized and targeted to lysosomes, where unlike other cell types it is transiently present. Cytokine secretion profiles and myelin phagocytosis reveal that ApoD has both long-term pre-conditioning effects on microglia as well as acute effects on these microglial immune functions, without significant modification of cell survival. ApoD-triggered cytokine signatures are stimuli (paraquat vs. Aβ oligomers) and sex-dependent. Acute exposure to ApoD induces microglia to switch from their resting state to a secretory and less phagocytic phenotype, while long-term absence of ApoD leads to attenuated cytokine induction and increased myelin uptake, supporting a role for ApoD as priming or immune training factor. This knowledge should help to advance our understanding of the complex responses of microglia during aging and neurodegeneration, where signals received along our lifespan are combined with damage-triggered acute signals, conditioning both beneficial roles and limitations of microglial functions.This work was supported by a Ministerio de Ciencia e Innovación grant PID2019-110911RB-I00/AEI/10.13039/501100011033 to MG and DS.202420242023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10366/154862reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)Inglésinfo:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1548622026-06-07T06:28:51Z |
| dc.title.none.fl_str_mv |
Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses |
| title |
Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses |
| spellingShingle |
Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses Corraliza-Gomez, Miriam acute response amyloid-beta endocytosis astrocyte-microglia crosstalk cytokine secretion immune memory membrane-binding protein microglia myelin phagocytosis amyloid-beta endocytosis Phagocytosis Immunologic Memory Microglia 6310.03 Enfermedad medicina |
| title_short |
Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses |
| title_full |
Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses |
| title_fullStr |
Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses |
| title_full_unstemmed |
Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses |
| title_sort |
Dual role of Apolipoprotein D as long-term instructive factor and acute signal conditioning microglial secretory and phagocytic responses |
| dc.creator.none.fl_str_mv |
Corraliza-Gomez, Miriam Bendito, Beatriz Sandonis-Camarero, David Mondejar-Duran, Jorge Villa, Miguel Poncela, Marta Valero, Jorge Sánchez, Diego Ganfornina, Maria Dolores |
| author |
Corraliza-Gomez, Miriam |
| author_facet |
Corraliza-Gomez, Miriam Bendito, Beatriz Sandonis-Camarero, David Mondejar-Duran, Jorge Villa, Miguel Poncela, Marta Valero, Jorge Sánchez, Diego Ganfornina, Maria Dolores |
| author_role |
author |
| author2 |
Bendito, Beatriz Sandonis-Camarero, David Mondejar-Duran, Jorge Villa, Miguel Poncela, Marta Valero, Jorge Sánchez, Diego Ganfornina, Maria Dolores |
| author2_role |
author author author author author author author author |
| dc.subject.none.fl_str_mv |
acute response amyloid-beta endocytosis astrocyte-microglia crosstalk cytokine secretion immune memory membrane-binding protein microglia myelin phagocytosis amyloid-beta endocytosis Phagocytosis Immunologic Memory Microglia 6310.03 Enfermedad medicina |
| topic |
acute response amyloid-beta endocytosis astrocyte-microglia crosstalk cytokine secretion immune memory membrane-binding protein microglia myelin phagocytosis amyloid-beta endocytosis Phagocytosis Immunologic Memory Microglia 6310.03 Enfermedad medicina |
| description |
Microglial cells are recognized as very dynamic brain cells, screening the environment and sensitive to signals from all other cell types in health and disease. Apolipoprotein D (ApoD), a lipid-binding protein of the Lipocalin family, is required for nervous system optimal function and proper development and maintenance of key neural structures. ApoD has a cell and state-dependent expression in the healthy nervous system, and increases its expression upon aging, damage or neurodegeneration. An extensive overlap exists between processes where ApoD is involved and those where microglia have an active role. However, no study has analyzed the role of ApoD in microglial responses. In this work, we test the hypothesis that ApoD, as an extracellular signal, participates in the intercellular crosstalk sensed by microglia and impacts their responses upon physiological aging or damaging conditions. We find that a significant proportion of ApoD-dependent aging transcriptome are microglia-specific genes, and show that lack of ApoD in vivo dysregulates microglial density in mouse hippocampus in an age-dependent manner. Murine BV2 and primary microglia do not express ApoD, but it can be internalized and targeted to lysosomes, where unlike other cell types it is transiently present. Cytokine secretion profiles and myelin phagocytosis reveal that ApoD has both long-term pre-conditioning effects on microglia as well as acute effects on these microglial immune functions, without significant modification of cell survival. ApoD-triggered cytokine signatures are stimuli (paraquat vs. Aβ oligomers) and sex-dependent. Acute exposure to ApoD induces microglia to switch from their resting state to a secretory and less phagocytic phenotype, while long-term absence of ApoD leads to attenuated cytokine induction and increased myelin uptake, supporting a role for ApoD as priming or immune training factor. This knowledge should help to advance our understanding of the complex responses of microglia during aging and neurodegeneration, where signals received along our lifespan are combined with damage-triggered acute signals, conditioning both beneficial roles and limitations of microglial functions. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2024 2024 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10366/154862 |
| url |
http://hdl.handle.net/10366/154862 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.source.none.fl_str_mv |
reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca instname:Universidad de Salamanca (USAL) |
| instname_str |
Universidad de Salamanca (USAL) |
| reponame_str |
GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| collection |
GREDOS. Repositorio Institucional de la Universidad de Salamanca |
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| repository.mail.fl_str_mv |
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1869411801736675328 |
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15.301603 |