UC San Diego
Removal of PHLPP2 Accentuates Injury-Induced Inflammation and Cell Death of Astrocytes
- Author(s): Welch, Lindsey Carroll
- Advisor(s): Purcell, Nicole H
- et al.
During an ischemic stroke, a blood clot obstructs the transport of essential nutrients to the brain, resulting in cell death (CDC 2018). The extent of injury following ischemic damage is a delicate balance between cell death and cell survival signals. Astrocytes are the most common glial cells found in the brain (Jakel and Dimou 2017). They provide metabolic and trophic support to neurons, and are pivotal responders to CNS (central nervous system) insult (Sofroniew and Vinters 2010). Survival of neurons depends on the coordinated efforts of the neurovascular unit and health of astrocytes. PHLPP (Pleckstrin Homology domain and Leucine rich repeat Protein Phosphatase) dephosphorylates and terminates the activity of several AGC kinases that are important for controlling cell growth, proliferation, and survival (Grzechnik and Newton 2016). We have previously reported that removal of the isoform PHLPP1 increases Akt activity in astrocytes and the brain, conferring protection following ischemic injury both in vitro and in vivo (Chen et al. 2013). However, the role of the PHLPP2 isoform in the brain and in astrocytes on signaling and injury is less well understood. To study the effect of PHLPP2 removal on signaling and inflammatory responses in the brain and astrocytes, I used extracts from whole brain homogenates and primary astrocytes isolated from PHLPP2 knock-out and wild type mice. To elucidate the effect of PHLPP2 removal on inflammatory gene expression, signaling, and cell death levels under conditions that mimic ischemic injury, I performed Western blotting, mRNA analysis, and an ELISA-based cell death assay. We show that unlike removal of PHLPP1, removal of PHLPP2 is detrimental under ischemic conditions in vitro. Our findings suggest that therapeutics that selectively silence PHLPP1, but not PHLPP2, are needed for treatment of ischemic stroke in order to reduce brain damage.