Microglial NMDA receptors drive pro‐inflammatory responses via PARP‐1/TRMP2 signaling

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.

Rapamycin Modulates the Proinflammatory Memory-Like Response of Microglia Induced by BAFF

“…As manifested in Figure 10 , the unprimed primary microglial cells displayed shortened cellular branches. In contrast, the BAFF-priming microglial cells showed an obvious enlarged cell body with thickening and retraction of cellular branches, which was defined as proinflammatory morphological activation ( 25 , 36 ). Microglial cells pretreated with rapamycin transformed into a morphology similar to the unprimed one.…”

“…Microglial morphology was assessed by phase-contrast microscopy based on previously described criteria ( 25 ). The cell morphology was observed using the Nexcope NIB410 microscope linked to the DLAIPU PUBLIC software (China) for image processing.…”

Blocking glycine receptors reduces neuroinflammation and restores neurotransmission in cerebellum through ADAM17-TNFR1-NF-κβ pathway

“…Microglia expresses most types of glutamate receptors, including NMDA receptors. Activation of NMDA receptors by glutamate in microglia leads to morphological activation and release of inflammatory mediators that promote microglial polarization [50,51]. Glutamate released from Purkinje neurons in hyperammonemic rats would also contribute to keep microglial activation.…”

Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer’s Disease

“…Also, the injection of Aβ into PARP-1 (−/−) mice or the inhibition of PARP-1 with PJ34 induced lower microglial activation compared to controls ( Kauppinen et al, 2011 ). Recent studies show that the toxicity of Aβ involves the activation of the transient receptor potential melastatin-related 2 (TRPM2) channel, a cation channel activated by ADP-ribose ( Miller, 2006 ; Alawieyah Syed Mortadza et al, 2018 ; Li and Jiang, 2018 ; Raghunatha et al, 2020 ). In studies in hippocampal neurons it is proposed that Aβ-generated ROS damage the DNA activating PARP-1 which in turn activates TRPM2 leading to Ca 2+ entry and mitochondrial dysfunction perpetuating the cycle ( Li and Jiang, 2018 ).…”

“…In a microglial cell line (BV2 cells) microglial activation induced by lipopolysaccharides (LPS) stimulation prompted PARP-1 enzymatic activity that enhanced microglial expression of NF-κB-dependent inflammatory cytokines (IL1β and TNF-α) ( Martínez-Zamudio and Ha, 2014 ). The signaling pathway maintaining microglial PARP−1 activation also involves the TRMP2 channel ( Raghunatha et al, 2020 ). In vivo experiments are in line with this evidence.…”