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Journal of Neuroinflammation

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Open Access 01-12-2012 | Research

Secreted phospholipase A₂-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding

Authors: Rubén Martín, Claudia Cordova, Maria L Nieto

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

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 A₂-IIA (sPLA₂-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 sPLA₂-IIA was examined by investigating its direct effects on microglial cells.

Methods

Primary and immortalized microglial cells were stimulated by sPLA₂-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 sPLA₂-IIA stimulated, in a time- and dose-dependent manner, their phagocytic and proliferative capabilities. sPLA₂-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 sPLA₂-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 sPLA₂-IIA.

Conclusion

These results support the hypothesis that sPLA₂-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 sPLA₂-IIA accumulation.

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Title: Secreted phospholipase A2-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding
Authors: Rubén Martín
Claudia Cordova
Maria L Nieto
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-154

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Secreted phospholipase A₂-IIA-induced a phenotype of activated microglia in BV-2 cells requires epidermal growth factor receptor transactivation and proHB-EGF shedding

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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