Cargando…
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...
Autores principales: | , , |
---|---|
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 |
_version_ | 1782248639626739712 |
---|---|
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. |
format | Online Article Text |
id | pubmed-3488565 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT martinruben secretedphospholipasea2iiainducedaphenotypeofactivatedmicrogliainbv2cellsrequiresepidermalgrowthfactorreceptortransactivationandprohbegfshedding AT cordovaclaudia secretedphospholipasea2iiainducedaphenotypeofactivatedmicrogliainbv2cellsrequiresepidermalgrowthfactorreceptortransactivationandprohbegfshedding AT nietomarial secretedphospholipasea2iiainducedaphenotypeofactivatedmicrogliainbv2cellsrequiresepidermalgrowthfactorreceptortransactivationandprohbegfshedding |