Microglial NMDA receptors drive pro‐inflammatory responses via PARP‐1/TRMP2 signaling. Issue 7 (8th February 2020)

• Record Type: Journal Article
• Authors: Raghunatha, Prajwal; Vosoughi, Amir; Kauppinen, Tiina M.; Jackson, Michael F.
• Is Part Of: Glia. Volume 68:Issue 7(2020)
• Page Start: 1421
• Page End: 1434
• Publication Date: 2020-02-08
• Subjects: microglia -- neuroinflammation -- NMDA receptors -- PARP‐1 -- TRPM2; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23790
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract: Chronic neuroinflammation driven by microglia is a characteristic feature associated with numerous neurodegenerative diseases. While acute inflammation can assist with recovery and repair, prolonged microglial pro‐inflammatory responses are known to exacerbate neurodegenerative processes. Yet, detrimental outcomes of extended microglial activation are counterbalanced by beneficial outcomes including phagocytosis and release of trophic factors promoting neuronal viability. Our past work has shown that the nuclear enzyme poly(ADP‐ribose) polymerase‐1 (PARP‐1) is a key signaling hub driving pro‐inflammatory microglia responses, but the signaling pathway maintaining PARP‐1 activation remains elusive. While best understood for its role in promoting DNA repair, our group has shown that PARP‐1 activity can be stimulated via Ca 2+ influx‐dependent ERK1/2‐mediated phosphorylation. However, to date, the route of Ca 2+ entry responsible for stimulating PARP‐1 has not been identified. A likely candidate is via Ca 2+ ‐permeable transient receptor potential melastatin 2 (TRPM2) channels activated downstream of PARP‐1 in a cascade that involves ADP‐ribose (ADPR) production by poly(ADP‐ribose) glycohydrolase (PARG). Here we demonstrate that NMDA receptor (NMDAR) stimulation in primary cultured microglia induces their proliferation, morphological activation and release of pro‐inflammatory mediators. These responses were contingent on the recruitment of PARP‐1, PARG and Ca 2+ permeable TRPM2 channels. Furthermore, we show that Ca 2+ influx is necessary to activate PARP‐1/TRPM2 signaling, in an ERK1/2‐dependent, but DNA damage independent, manner. Our findings, showing that PARP‐1/TRPM2 mediate the pro‐inflammatory effects of NMDAR stimulation, provides a unifying mechanism linking elevated glutamate levels to chronic neuroinflammation. Abstract : The signaling pathway that maintains microglial pro‐inflammatory responses during under conditions of aberrant NMDAR stimulation. Microglial NMDAR‐initiated pro‐inflammatory responses require PARP‐1, maintained active through TRPM2‐mediated Ca 2+ feedback and ERK1/2. This signaling axis provides a mechanism linking chronically elevated glutamate to sustained inflammation.