A critical role of TRPM2 channel in Aβ₄₂‐induced microglial activation and generation of tumor necrosis factor‐α

Abstract

Amyloid β (Aβ)-induced neuroinflammation plays an important part in Alzheimer's disease (AD). Emerging evidence supports a role for the transient receptor potential melastatin-related 2 (TRPM2) channel in Aβ-induced neuroinflammation, but how Aβ induces TRPM2 channel activation and this relates to neuroinflammation remained poorly understood. We investigated the mechanisms by which Aβ activates the TRPM2 channel in microglial cells and the relationships to microglial activation and generation of tumor necrosis factor-α (TNF-α), a key cytokine implicated in AD. Exposure to 10-300 nM Aβ induced concentration-dependent microglial activation and generation of TNF-α that were ablated by genetically deleting (TRPM2 knockout ;TRPM2-KO) or pharmacologically inhibiting the TRPM2 channel, revealing a critical role of this channel in Aβ -induced microglial activation and generation of TNF-α. Mechanistically, Aβ activated the TRPM2 channel via stimulating generation of reactive oxygen species (ROS) and activation of poly(ADPR) polymerase-1 (PARP-1). Aβ -induced generation of ROS and activation of PARP-1 and TRPM2 channel were suppressed by inhibiting protein kinase C (PKC) and NADPH oxidases (NOX). Aβ -induced activation of PARP-1 and TRPM2 channel was also reduced by inhibiting PYK2 and MEK/ERK. Aβ -induced activation of PARP-1 was attenuated by TRPM2-KO and moreover, the remaining PARP-1 activity was eliminated by inhibiting PKC and NOX, but not PYK2 and MEK/ERK. Collectively, our results suggest that PKC/NOX-mediated generation of ROS and subsequent activation of PARP-1 play a role in Aβ -induced TRPM2 channel activation and TRPM2-dependent activation of the PYK2/MEK/ERK signalling pathway acts as a positive feedback to further facilitate activation of PARP-1 and TRPM2 channel. These findings provide novel insights into the mechanisms underlying Aβ-induced AD-related neuroinflammation.

Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signaling

“…In this study, we have also shed light on the downstream signaling pathways in Piezo1‐dependent stimulation of hDP‐MSC migration as well as ATP‐induced P2 receptor‐dependent stimulation of hDP‐MSC migration reported in our previous study . PYK2 is a well‐recognized signaling mechanism transducing Ca 2+ ‐dependent induction of the MEK/ERK signaling pathway . Our results from hDP‐MSCs from three donors showed that Yoda1‐induced cell migration was prevented by inhibiting PYK2 (Figure A‐D) and MEK/ERK (Figure E‐H).…”

“…It has been proposed that the Piezo1 channel mediates ultrasound‐induced activation of the MEK/ERK signaling pathway in rat DP‐MSCs . The proline‐rich tyrosine kinase 2 (PYK2) is well‐known as a signaling molecule downstream of intracellular Ca 2+ and plays a critical role in mediating Ca 2+ ‐dependent induction of the MEK/ERK pathway in monocyte, microglial, and neuronal cells . There is evidence for involvement of PYK2 in cancer cell migration, but it is unclear whether PYK2 plays a role in the regulation of MSC migration.…”

Reversal of β-amyloid induced microglial toxicityin vitroby activation of Fpr2/3

“…Here, we report that alongside its well-characterised function in resolving inflammation and efferocytosis [40], Fpr2/3 activation can reverse oAβ-induced ROS production through deactivation of NADPH oxidase activity. Activation of microglial NADPH oxidase by oAβ is well supported [41,42], and may be critical in triggering neuroinflammation, given the damaging effects of oxidative stress for neurones, as has been reported in traumatic brain injury [43]. Future work will determine whether the in vitro findings we report here can be extended to the in vivo situation, but if so, they suggest that the use of Fpr2/3 agonists capable of reversing NADPH oxidase activation may be of therapeutic potential for AD.…”

Physiological and Pathophysiological Roles of Transient Receptor Potential Channels in Microglia-Related CNS Inflammatory Diseases

“…45) More recently, Alawieyah Syed Mortadza et al report that exposure to 10-300 nM Aβ42 induces concentration-dependent microglial activation and generation of TNFα that are ablated by genetically deleting of TRPM2 or pharmacologically inhibiting TRPM2, revealing a critical role of TRPM2 in Aβ42-induced microglial activation. 46) These reports shed light on our understanding of the mechanisms of chronic cerebral hypoperfusion-related inflammation, and suggest a novel therapeutic target for the treatment of cognitive impairment in CNS diseases.…”