| Title |
Phosphoinositide 3-Kinase γ Restrains Neurotoxic Effects of Microglia After Focal Brain Ischemia
|
|---|---|
| Published in |
Molecular Neurobiology, October 2015
|
| DOI | 10.1007/s12035-015-9472-z |
| Pubmed ID | |
| Authors |
Caroline Schmidt, Christiane Frahm, Nadine Schneble, Jörg P. Müller, Michael Brodhun, Irene Franco, Otto W. Witte, Emilio Hirsch, Reinhard Wetzker, Reinhard Bauer |
| Abstract |
Phosphoinositide 3-kinase γ (PI3Kγ) is linked to neuroinflammation and phagocytosis. This study was conducted to elucidate conjectural differences of lipid kinase-dependent and kinase-independent functions of PI3Kγ in the evolvement of brain damage induced by focal cerebral ischemia/reperfusion. Therefore, PI3Kγ wild-type, knockout, and kinase-dead mice were subjected to middle cerebral artery occlusion followed by reperfusion. Tissue damage and cellular composition were assessed by immunohistochemical stainings. In addition, microglial cells derived from respective mouse genotypes were used for analysis of PI3Kγ effects on phagocytic activity, matrix metalloproteinase-9 release, and cAMP content under conditions of oxygen/glucose deprivation and recovery. Brain infarction was more pronounced in PI3Kγ-knockout mice compared to wild-type and kinase-dead mice 48 h after reperfusion. Immunohistochemical analyses revealed a reduced amount of galectin-3/MAC-2-positive microglial cells indicating that activated phagocytosis was reduced in ischemic brains of knockout mice. Cell culture studies disclosed enhanced metalloproteinase-9 secretion in supernatants derived from microglia of PI3Kγ-deficient mice after 2-h oxygen/glucose deprivation and 48-h recovery. Furthermore, PI3Kγ-deficient microglial cells showed a failed phagocytic activation throughout the observed recovery period. Lastly, PI3Kγ-deficient microglia exhibited strongly increased cAMP levels in comparison with wild-type microglia or cells expressing kinase-dead PI3Kγ after oxygen/glucose deprivation and recovery. Our data suggest PI3Kγ kinase activity-independent control of cAMP phosphodiesterase as a crucial mediator of microglial cAMP regulation, MMP-9 expression, and phagocytic activity following focal brain ischemia/recirculation. The suppressive effect of PI3Kγ on cAMP levels appears critical for the restriction of ischemia-induced immune cell functions and in turn tissue damage. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 26 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 1 | 4% |
| Unknown | 25 | 96% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 7 | 27% |
| Student > Master | 5 | 19% |
| Student > Ph. D. Student | 5 | 19% |
| Professor | 2 | 8% |
| Researcher | 2 | 8% |
| Other | 2 | 8% |
| Unknown | 3 | 12% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 6 | 23% |
| Biochemistry, Genetics and Molecular Biology | 4 | 15% |
| Agricultural and Biological Sciences | 4 | 15% |
| Neuroscience | 4 | 15% |
| Immunology and Microbiology | 1 | 4% |
| Other | 3 | 12% |
| Unknown | 4 | 15% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 11 October 2015.
All research outputs
#20,294,248
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Outputs from Molecular Neurobiology
#2,792
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#233,836
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Outputs of similar age from Molecular Neurobiology
#77
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