Piezo1 regulates calcium oscillations and cytokine release from astrocytes

Sheridan, Graham K.; Velasco‐Estevez, María; Dev, Kumlesh K.; Rolle, Sara O.; Mampay, Myrthe

Abstract

Astrocytes are important for information processing in the brain and they achieve this by fine‐tuning neuronal communication via continuous uptake and release of biochemical modulators of neurotransmission and synaptic plasticity. Often overlooked are their important functions in mechanosensation. Indeed, astrocytes can detect pathophysiological changes in the mechanical properties of injured, ageing, or degenerating brain tissue. We have recently shown that astrocytes surrounding mechanically‐stiff amyloid plaques upregulate the mechanosensitive ion channel, Piezo1. Moreover, ageing transgenic Alzheimer's rats harboring a chronic peripheral bacterial infection displayed enhanced Piezo1 expression in amyloid plaque‐reactive astrocytes of the hippocampus and cerebral cortex. Here, we have shown that the bacterial endotoxin, lipopolysaccharide (LPS), also upregulates Piezo1 in primary mouse cortical astrocyte cultures in vitro. Activation of Piezo1, via the small molecule agonist Yoda1, enhanced Ca2+ influx in both control and LPS‐stimulated astrocytes. Moreover, Yoda1 augmented intracellular Ca2+ oscillations but decreased subsequent Ca2+ influx in response to adenosine triphosphate (ATP) stimulation. Neither blocking nor activating Piezo1 affected cell viability. However, LPS‐stimulated astrocyte cultures exposed to the Piezo1 activator, Yoda1, migrated significantly slower than reactive astrocytes treated with the mechanosensitive channel‐blocking peptide, GsMTx4. Furthermore, our data show that activating Piezo1 channels inhibits the release of cytokines and chemokines, such as IL‐1β, TNFα, and fractalkine (CX3CL1), from LPS‐stimulated astrocyte cultures. Taken together, our results suggest that astrocytic Piezo1 upregulation may act to dampen neuroinflammation and could be a useful drug target for neuroinflammatory disorders of the brain.

Citation

Sheridan, G. K., Velasco‐Estevez, M., Dev, K. K., Rolle, S. O., & Mampay, M. (2020). Piezo1 regulates calcium oscillations and cytokine release from astrocytes. Glia, 68(1), 145-160. https://doi.org/10.1002/glia.23709

• Journal Article Type: Article
• Acceptance Date: Aug 7, 2019
• Online Publication Date: Aug 21, 2019
• Publication Date: 2020-01
• Deposit Date: Sep 6, 2019
• Publicly Available Date: Aug 22, 2020
• Journal: Glia
• Print ISSN: 0894-1491
• Electronic ISSN: 1098-1136
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 68
• Issue: 1
• Pages: 145-160
• DOI: https://doi.org/10.1002/glia.23709
• Keywords: Cellular and Molecular Neuroscience; Neurology
• Public URL: https://nottingham-repository.worktribe.com/output/2573544
• Publisher URL: https://onlinelibrary.wiley.com/doi/full/10.1002/glia.23709
• Additional Information: This is the peer reviewed version of the following article: Velasco‐Estevez, M, Rolle, SO, Mampay, M, Dev, KK, Sheridan, GK. Piezo1 regulates calcium oscillations and cytokine release from astrocytes. Glia. 2019; 1– 16, which has been published in final form at https://doi.org/10.1002/glia.23709. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.