Restoration of PP2A levels in inflamed microglial cells: Important for neuroprotective M2 microglial viability.
Toxicol Appl Pharmacol
; 409: 115294, 2020 12 15.
Article
in En
| MEDLINE
| ID: mdl-33069748
ABSTRACT
PP2A, a trimeric Serine/Threonine Protein Phosphatase 2A highly expressed in brain, is a master regulator of cellular functions. Reduction in PP2A activity has been linked to progression of microglial mediated neuroinflammatory diseases. Inflammatory conditions are characterized by increased population of CD86+ve M1 cells and a therapeutic strategy to polarize microglial cells towards CD206+ve M2 cells is the need of hour. In this paper we analyzed A whether the level of PP2A is altered in CD86+ve cells, B whether FTY720, a known modulator of PP2A, is able to restore the level of PP2A in inflamed CD86+ve cells. Results revealed that PP2A activity was significantly diminished in inflamed cells but the surprising observation was the cell viability of only 35.99% upon FTY720 treatment in inflamed cells lacking basal PP2A activity. A sharp increase at mRNA level of CD95 and ASK-1 indicated that apoptosis occurred in these cells through CD95/ASK-1/JNK pathway. Importantly, flow cytometric analysis revealed apoptosis of not only CD86+ve cells but also CD206+ve cells. Previous studies have reported that FTY720 polarizes microglial cells towards M2 states; however apoptosis of M2 cells was not studied. As western blot analysis revealed that FTY720 failed to completely restore PP2A, another PP2A modulator, Memantine, was used for co-treatment. Upon co-treatment, the level of PP2A was completely restored and also viability of microglial cells was significantly improved with a significant reduction in apoptosis of M2 cells. These findings suggest that co-treatment strategy may prove beneficial to balance M1/M2 microglial population, thereby improving neuronal functions.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Survival
/
Microglia
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Protein Phosphatase 2
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Neuroprotection
/
Inflammation
Limits:
Animals
Language:
En
Journal:
Toxicol Appl Pharmacol
Year:
2020
Type:
Article
Affiliation country:
India