Biology subjects

Pagliarini, M.

Publications and source records attributed to Pagliarini, M..

3 recordsLinked to original sources

bioRxiv2026

Loss of C3 and CD14 reduces region-specific neuroinflammation in a murine polytrauma model

BackgroundTraumatic brain injury (TBI) together with non-cerebral injuries characterizes the TBI-polytrauma (P-TBI) constellation, which is associated with acute neurological deterioration, delirium and unfavourable prognosis. It is hypothesized that systemic inflammatory mediators my enhances the focal, cerebral neuroimmune reaction with overall detrimental consequences, in particular in terms of acute microglial reactivity. MethodsWe explored the role of the Complement factor 3 (C3) and of the TLR-co receptor cluster of differentiation (CD14) in a murine polytrauma model that involves a mild TBI together with femur fracture, blunt thorax trauma and resuscitated haemorrhagic shock, making use of mice genetically lacking either C3, CD14 or both. ResultsWe show that P-TBI results in a rapid (4h) and brain-wide induction of inflammatory cytokines, although with distinct profiles (TNF and CCL2 having brain-wide involvement and IL-1{beta} restricted to ipsilateral cortex and striatum). TNF and CCL2 mRNA as well as protein synthesis were upregulated in microglia upon P-TBI in cortex, hippocampus and striatum which was fully abolished in the C3-/-CD14-/-animals. The analysis of single-KO animals revealed that induction of TNF and CCL2 was prevented in animals lacking C3, but not CD14, in the contralateral cortex and striatum, with an abolishment in hippocampus in mice lacking both C3 and CD14. In the cortical area of focal lesion neither C3 nor CD14 affected the induction of pro-inflammatory cytokines. ConclusionThus, C3 and CD14 are dispensable for the acute cytokine response to P-TBI in the site of injury but play differential roles across the cortex, hippocampus and striatum for the induction of cytokines in the non-injured parenchyma and in particular in microglia. Thus, interventions on C3 (mainly) and/or CD14 may reduce the encephalopathy risk associated with P-TBI but not the acute response in the injury site, where additional DAMP signalling may offer redundant activation pathways.

neuroscience↗

bioRxiv2025

Basophils activate splenic B cells and Dendritic cells via IL-13 signaling in acute Traumatic Brain Injury

Peripheral consequences following traumatic brain injury (TBI) are characterized by both systemic inflammatory responses and autonomic dysregulation, with almost all peripheral organs affected. One of the main immune regulatory organs, the spleen, shows high interaction with the brain which is controlled by both circulating mediators as well as autonomic fibers targeting splenic immune cells. The brain-spleen axis does not function as a one-way street, it also shows reciprocal effects where the spleen affects neuroinflammatory and cognitive functions post injury. To date, systemic and splenic inflammatory responses are measured by cells or mediators located in circulation. Nevertheless, most of the signaling and inflammation post injury takes place in the organs. Therefore, we set out to investigate the early signaling landscape in the spleen following TBI, using phospho-proteomic signaling approaches and immunofluorescence stainings to investigate novel molecular and cellular players. Based on the signaling signature, we found a rapid influx of basophil granulocytes towards the spleen, which are recruited via CXCL1 expressed by B-cells and dendritic cells. The basophils activate B cells and dendritic cells (DCs) via the IL-13/IL-13Ra1 signaling pathway to enhance protein translation through the long non-coding RNA NORAD. The early recruitment of basophils and subsequent activation of B cells and DCs, is short lived and sets at 3dpi. Interestingly, the rapid recruitment of basophils is inhibited by ethanol intoxication in TBI. In conclusion, basophils recruitment to the spleen may serve as an early mediator of systemic inflammatory responses to TBI with potential implications for research on biomarkers and therapeutic targets.

neuroscience↗

bioRxiv2025

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

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.

neuroscience↗