EGFR activation correlates with intracranial pressure and outcome in a mixed intracranial bleeding porcine model

Zhao, Z.; Hoffmann, A.; Groeger, M.; Kress, S.; Muenz, F.; Sun, F.; Merz, T.; Sheer, M.; Calzia, E.; Oezkan, B.; Radermacher, P.; Roselli, F.; Kapapa, T.; Pagliarini, M.

doi:10.1101/2025.05.02.651431

bioRxiv · 10.1101/2025.05.02.651431

EGFR activation correlates with intracranial pressure and outcome in a mixed intracranial bleeding porcine model

Zhao, Z.·Hoffmann, A.·Groeger, M.·Kress, S.·Muenz, F.·Sun, F.·Merz, T.·Sheer, M.·Calzia, E.·Oezkan, B.·Radermacher, P.·Roselli, F.·Kapapa, T.·Pagliarini, M.

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Abstract

Intracranial hypertension is a major driver of secondary injury after acute subdural hematoma (ASDH), yet how mechanical stress is translated into neuroinflammatory signaling remains poorly understood. Here, we identify a mechanosensitive astrocyte signaling pathway that links elevated intracranial pressure (ICP) to inflammatory amplification in the injured brain. Using a clinically relevant porcine ASDH model combined with mechanistic studies in human iPSC-derived astrocytes, we demonstrate that sustained ICP elevation induces bilateral neuroinflammation together with coordinated upregulation of mechanosensitive ion channels and receptor tyrosine kinase (RTK) pathways. Integrative analysis of molecular and physiological datasets identified astrocytes as the principal cellular responders to ICP and revealed epidermal growth factor receptor (EGFR) as the astrocyte-associated RTK most strongly correlated with ICP dynamics, inflammatory chemokine expression, and survival. Pharmacological activation of the mechanosensitive channel Piezo1 in human astrocytes was sufficient to trigger EGFR internalization, site-specific phosphorylation, and ERK signaling, promoting structural remodeling and robust induction of pro-inflammatory mediators including CCL2, IL-6, and IL-8. Conversely, EGFR inhibition attenuated inflammatory signaling while enhancing astrocytic programs associated with water handling and edema containment. In vivo, increased expression of EGFR ligands together with elevated EGFR phosphorylation supported sustained pathway engagement following ASDH, and correlation analyses linked Piezo1 expression and EGFR activation with ICP severity and adverse outcome. Together, these findings define a mechanotransduction axis in which astrocytic Piezo1 signaling integrates mechanical stress with EGFR-dependent neuroimmune responses, positioning EGFR as a translationally accessible target to modulate inflammation-driven secondary brain injury.

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Zhao, Z., Hoffmann, A., Groeger, M., Kress, S., Muenz, F., Sun, F., Merz, T., Sheer, M., Calzia, E., Oezkan, B., Radermacher, P., Roselli, F., Kapapa, T., Pagliarini, M.. 2025-05-07. EGFR activation correlates with intracranial pressure and outcome in a mixed intracranial bleeding porcine model. https://doi.org/10.1101/2025.05.02.651431

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