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Secreted phospholipase A(2)-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding

BACKGROUND: Activation of microglia, the primary component of the innate immune response in the brain, is a hallmark of neuroinflammation in neurodegenerative disorders, including Alzheimer’s disease (AD) and other pathological conditions such as stroke or CNS infection. In response to a variety of...

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Autores principales: Martín, Rubén, Cordova, Claudia, Nieto, Maria L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488565/
https://www.ncbi.nlm.nih.gov/pubmed/22747893
http://dx.doi.org/10.1186/1742-2094-9-154
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author Martín, Rubén
Cordova, Claudia
Nieto, Maria L
author_facet Martín, Rubén
Cordova, Claudia
Nieto, Maria L
author_sort Martín, Rubén
collection PubMed
description BACKGROUND: Activation of microglia, the primary component of the innate immune response in the brain, is a hallmark of neuroinflammation in neurodegenerative disorders, including Alzheimer’s disease (AD) and other pathological conditions such as stroke or CNS infection. In response to a variety of insults, microglial cells produce high levels of inflammatory cytokines that are often involved in neuronal injury, and play an important role in the recognition, engulfment, and clearance of apoptotic cells and/or invading microbes. Secreted phospholipase A(2)-IIA (sPLA(2)-IIA), an enzyme that interacts with cells involved in the systemic immune/inflammatory response, has been found up-regulated in the cerebrospinal fluid and brain of AD patients. However, despite several approaches, its functions in mediating CNS inflammation remain unknown. In the present study, the role of sPLA(2)-IIA was examined by investigating its direct effects on microglial cells. METHODS: Primary and immortalized microglial cells were stimulated by sPLA(2)-IIA in order to characterize the cytokine-like actions of the phospholipase. The hallmarks of activated microglia analyzed include: mitogenic response, phagocytic capabilities and induction of inflammatory mediators. In addition, we studied several of the potential molecular mechanisms involved in those events. RESULTS: The direct exposure of microglial cells to sPLA(2)-IIA stimulated, in a time- and dose-dependent manner, their phagocytic and proliferative capabilities. sPLA(2)-IIA also triggered the synthesis of the inflammatory proteins COX-2 and TNFα. In addition, EGFR phosphorylation and shedding of the membrane-anchored heparin-binding EGF-like growth factor (pro-HB-EGF) ectodomain, as well as a rapid activation/phosphorylation of the classical survival proteins ERK, P70S6K and rS6 were induced upon sPLA(2)-IIA treatment. We further demonstrated that the presence of an EGFR inhibitor (AG1478), a matrix metalloproteinase inhibitor (GM6001), an ADAM inhibitor (TAPI-1), and a HB-EGF neutralizing antibody abrogated the phenotype of activated microglia induced by the sPLA(2)-IIA. CONCLUSION: These results support the hypothesis that sPLA(2)-IIA may act as a potent modulator of microglial functions through its ability to induce EGFR transactivation and HB-EGF release. Accordingly, pharmacological modulation of EGFR might be a useful tool for treating neuroinflammatory diseases characterized by sPLA(2)-IIA accumulation.
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spelling pubmed-34885652012-11-05 Secreted phospholipase A(2)-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding Martín, Rubén Cordova, Claudia Nieto, Maria L J Neuroinflammation Research BACKGROUND: Activation of microglia, the primary component of the innate immune response in the brain, is a hallmark of neuroinflammation in neurodegenerative disorders, including Alzheimer’s disease (AD) and other pathological conditions such as stroke or CNS infection. In response to a variety of insults, microglial cells produce high levels of inflammatory cytokines that are often involved in neuronal injury, and play an important role in the recognition, engulfment, and clearance of apoptotic cells and/or invading microbes. Secreted phospholipase A(2)-IIA (sPLA(2)-IIA), an enzyme that interacts with cells involved in the systemic immune/inflammatory response, has been found up-regulated in the cerebrospinal fluid and brain of AD patients. However, despite several approaches, its functions in mediating CNS inflammation remain unknown. In the present study, the role of sPLA(2)-IIA was examined by investigating its direct effects on microglial cells. METHODS: Primary and immortalized microglial cells were stimulated by sPLA(2)-IIA in order to characterize the cytokine-like actions of the phospholipase. The hallmarks of activated microglia analyzed include: mitogenic response, phagocytic capabilities and induction of inflammatory mediators. In addition, we studied several of the potential molecular mechanisms involved in those events. RESULTS: The direct exposure of microglial cells to sPLA(2)-IIA stimulated, in a time- and dose-dependent manner, their phagocytic and proliferative capabilities. sPLA(2)-IIA also triggered the synthesis of the inflammatory proteins COX-2 and TNFα. In addition, EGFR phosphorylation and shedding of the membrane-anchored heparin-binding EGF-like growth factor (pro-HB-EGF) ectodomain, as well as a rapid activation/phosphorylation of the classical survival proteins ERK, P70S6K and rS6 were induced upon sPLA(2)-IIA treatment. We further demonstrated that the presence of an EGFR inhibitor (AG1478), a matrix metalloproteinase inhibitor (GM6001), an ADAM inhibitor (TAPI-1), and a HB-EGF neutralizing antibody abrogated the phenotype of activated microglia induced by the sPLA(2)-IIA. CONCLUSION: These results support the hypothesis that sPLA(2)-IIA may act as a potent modulator of microglial functions through its ability to induce EGFR transactivation and HB-EGF release. Accordingly, pharmacological modulation of EGFR might be a useful tool for treating neuroinflammatory diseases characterized by sPLA(2)-IIA accumulation. BioMed Central 2012-07-02 /pmc/articles/PMC3488565/ /pubmed/22747893 http://dx.doi.org/10.1186/1742-2094-9-154 Text en Copyright ©2012 Martín et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Martín, Rubén
Cordova, Claudia
Nieto, Maria L
Secreted phospholipase A(2)-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding
title Secreted phospholipase A(2)-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding
title_full Secreted phospholipase A(2)-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding
title_fullStr Secreted phospholipase A(2)-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding
title_full_unstemmed Secreted phospholipase A(2)-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding
title_short Secreted phospholipase A(2)-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding
title_sort secreted phospholipase a(2)-iia-induced a phenotype of activated microglia in bv-2 cells requires epidermal growth factor receptor transactivation and prohb-egf shedding
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488565/
https://www.ncbi.nlm.nih.gov/pubmed/22747893
http://dx.doi.org/10.1186/1742-2094-9-154
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