Piezo1 regulates calcium oscillations and cytokine release from astrocytes

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.

Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response

“…PIEZO1 channels are critical for vascular remodelling, including angiogenesis, and have implications for hypertension, aneurysms and stroke [54][55][56][57] . These channels prevent microglial activation by pro-inflammatory cytokines and chemokines, including IL-1β and TNF-α, in response to neurodegenerative amyloid-beta plaques and ischemic events [58][59][60][61] . Despite generally low PIEZO1 expression levels in the brain, the rs12597726 A-allele is associated with lower PIEZO1 expression, which may ultimately contribute to higher inflammation and non-response (see Supplementary Figs.…”

Inhibition of Piezo1 attenuates demyelination in the central nervous system

“…We have recently found that Yoda‐1 increases Ca 2+ influx into primary mouse astrocytes and triggers Ca 2+ release from intracellular stores, particularly under inflammatory conditions (i.e., after 24 hr exposure to 100 ng/ml lipopolysaccharide) (Velasco‐Estevez, Rolle, Mampay, Dev, & Sheridan, ). Therefore, we hypothesize that overactivation of neuronal Piezo1 in cerebellar slice cultures may trigger excitotoxic levels of calcium entry into CNS axons which, in turn, could cause the release Ca 2+ from intracellular stores and activation of the Ca 2+ dependent protease, calpain, which is known to be involved in LPC‐mediated demyelination (Fu et al, ).…”

Vasculo-Neuronal Coupling and Neurovascular Coupling at the Neurovascular Unit: Impact of Hypertension

“…While evidence supports mechanosensitivity in astrocytes, how this might influence neurovascular interactions is unclear, as these processes remain largely unexplored. Mechanostimulus-induced changes in astrocytic Ca 2+ could be attributable to a number of different ion channels, including P2 × 7 ( Beckel et al, 2014 ; Albalawi et al, 2017 ), TRPV4 ( Ryskamp et al, 2011 ; Dunn et al, 2013 ; Choi et al, 2015 ), Piezo1 ( Choi et al, 2015 ; Velasco-Estevez et al, 2020 ), and pannexin1 ( Minelli et al, 2007 ; Suadicani et al, 2012 ). Evidence also supports the idea that mechanical stimulation causes the release of adenosine in the brain.…”