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

Olde Heuvel, F.; Pagliarini, M.; Sun, F.; Lupu, L.; Zhao, Z.; Cui, L.; Halbgebauer, R.; Mannes, M.; Boeckers, T.; Lien, E.; Mollnes, T. E.; Huber-Lang, M.; Roselli, F.

doi:10.64898/2026.03.13.711583

bioRxiv · 10.64898/2026.03.13.711583

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

Olde Heuvel, F.·Pagliarini, M.·Sun, F.·Lupu, L.·Zhao, Z.·Cui, L.·Halbgebauer, R.·Mannes, M.·Boeckers, T.·Lien, E.·Mollnes, T. E.·Huber-Lang, M.·Roselli, F.

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Abstract

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.

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Olde Heuvel, F., Pagliarini, M., Sun, F., Lupu, L., Zhao, Z., Cui, L., Halbgebauer, R., Mannes, M., Boeckers, T., Lien, E., Mollnes, T. E., Huber-Lang, M., Roselli, F.. 2026-03-17. Loss of C3 and CD14 reduces region-specific neuroinflammation in a murine polytrauma model. https://doi.org/10.64898/2026.03.13.711583

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