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Life sciences · Journal article
Glia · September 1, 2026
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This preclinical study demonstrates that microglia-derived pro-inflammatory cytokines (IL-1α, IL-1β, TNF-α) upregulate Piezo1 expression in astrocytes via a paracrine signaling axis, and that astrocytic Piezo1 exerts context-dependent anti-inflammatory effects. The findings are supported by in vitro experiments with rodent and human cells and confirmed in vivo in 5xFAD transgenic mice, but lack quantitative effect sizes, statistical significance, and clinical translation.
In vitro primary culture experiments and transgenic mouse study. Primary rodent and human astrocytes; primary rodent microglia; 5xFAD transgenic mice (Alzheimer's disease model). Intervention: Inflammatory stimuli (LPS, oligomeric amyloid-β), microglia conditioned media, pro-inflammatory cytokines (IL-1α, IL-1β, TNF-α), Piezo1 activation (Yoda2), Piezo1 knockdown, microglial depletion. Compared with: Basal (unstimulated) conditions; cytokine pretreatment conditions; wild-type controls (implied for 5xFAD).
Direct LPS or oAβ exposure to astrocytes had minimal impact on Piezo1 expression; LPS/oAβ on microglia increased microglial Piezo1 and conditioned media upregulated astrocytic Piezo1 Microglia-derived IL-1α, IL-1β, and TNF-α directly enhanced Piezo1 expression and Piezo1-mediated Ca2+ signaling in rodent and human astrocytes Microglial depletion in 5xFAD mice consistently and substantially reduced astrocytic Piezo1 expression in vivo
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This work elucidates a novel mechanistic pathway linking microglial activation to astrocyte mechanosensitivity in neuroinflammation, potentially relevant to Alzheimer's disease and other brain disorders. However, the absence of quantified effect sizes, sample sizes, and statistical analysis limits immediate clinical interpretation; further validation in human tissues or patient-derived models is needed.
Mechanistic in vitro and transgenic mouse study identifying a microglia-astrocyte signaling axis regulating Piezo1 and inflammatory responses, but lacking clinical validation or human disease models.
As stated by the source record.
This work elucidates a novel mechanistic pathway linking microglial activation to astrocyte mechanosensitivity in neuroinflammation, potentially relevant to Alzheimer's disease and other brain disorders. However, the absence of quantified effect sizes, sample sizes, and statistical analysis limits immediate clinical interpretation; further validation in human tissues or patient-derived models is needed.
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Structural tissue alterations in numerous brain disorders can initiate mechanosensory signaling pathways and influence neuropathology. Astrocytes are highly mechanosensitive cells that play essential roles in maintaining brain homeostasis; however, the molecular mechanisms underlying astrocyte mechanosensation during pathological conditions remain largely unexplored. In this study, we investigated how the expression of the mechanosensitive ion channel Piezo1 in astrocytes is modulated by inflammatory triggers. We found that direct exposure of primary astrocyte cultures to inflammatory stimuli, including lipopolysaccharide (LPS) or oligomeric amyloid-β (oAβ), had minimal impact on astrocytic Piezo1 expression. In contrast, when LPS or oAβ were applied to primary microglia cultures, Piezo1 expression was increased in microglia, and conditioned media from these microglia cultures significantly upregulated Piezo1 expression in astrocytes. We further identified that microglia released pro-inflammatory cytokines (IL-1α, IL-1β, and TNF-α) that can directly enhance Piezo1 expression and Piezo1-mediated Ca2+ signaling in both rodent and human astrocytes. Microglial depletion in 5xFAD mice consistently and substantially reduced astrocytic Piezo1 expression in vivo, supporting the physiological relevance of this microglia-astrocyte signaling axis during pathology. Activation of Piezo1 with Yoda2 did not alter astrocytic inflammatory gene expression under basal conditions but reduced TNF-α, CCL2, and C3 expression following cytokine pretreatment. Conversely, Piezo1 knockdown increased GFAP expression at baseline and enhanced pro-inflammatory gene expression under cytokine stimulation, indirectly promoting microglial activation. These findings demonstrate that astrocytic Piezo1 expression is regulated by microglia-derived inflammatory signals and plays a context-dependent role in modulating astrocyte reactivity and neuroinflammatory responses.
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