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Publications

Journal Article Epublish

PubMed: 42786300 DOI: 10.1007/s00011-026-02367-7

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

Inflamm Res 75(1)

Authors: Florian Olde Heuvel, Marica Pagliarini, Fan Sun, Ludmila Lupu, Zongren Zhao, Likun Cui, Jin Zhang, Rebecca Halbgebauer, Marco Mannes, Tobias Maria Boeckers, Bernd Knöll, Egil Lien, Tom Eirik Mollnes, Markus Huber-Lang, Francesco Roselli

Affiliations

  • Department of Neurology, UIm University, Ulm, Germany.
  • Department of Neurology, UIm University, Ulm, Germany. German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany.
  • Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany.
  • Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany.
  • German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany.
  • Institute of Neurobiochemistry, Ulm University, Ulm, Germany.
  • Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Department of Immunology, Oslo University Hospital, Oslo, Norway.
  • Research Laboratory, Nordland Hospital Trust, Bodoe, Norway.
  • Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany.
  • Institute of Clinical and Experimental Trauma Immunology, Center Center for Biomedical Research (ZBF), Ulm University Medical, Helmholtzstrasse 8/1, 89081, Ulm, Germany.
  • Department of Neurology, UIm University, Ulm, Germany. German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany. Center for Biomedical Research (ZBF), Ulm University, Helmholtzstrasse 8/1, 89081, Ulm, Germany.

Abstract

BACKGROUND

TBI-polytrauma (P-TBI) is associated with acute neurological deterioration, delirium, and poor prognosis. Systemic inflammatory mediators are thought to amplify the cerebral neuroimmune response, particularly microglial activation, with detrimental consequences.

METHODS

We investigated the roles of complement factor C3 and the TLR co-receptor CD14 in a murine polytrauma model combining mild TBI with femur fracture, blunt thorax trauma, and resuscitated haemorrhagic shock, using mice lacking C3, CD14, or both.

RESULTS

P-TBI induced a rapid, brain-wide increase in inflammatory cytokines with region-specific patterns. TNF and CCL2 mRNA were upregulated in microglia in the cortex, hippocampus, and striatum, and this response was abolished in C3 -/-CD14 -/- mice. Analysis of single knockouts showed that cytokine induction depended on CD14 in the cortex, C3 in the striatum, and both in the hippocampus. In contrast, neither C3 nor CD14 influenced cytokine induction at the cortical lesion site. Interestingly, neuronal cFOS responses showed an inverse regional C3/CD14 dependency compared with inflammatory cytokine responses, with a cortical C3 dependency and striatal CD14 dependency.

CONCLUSION

Thus, C3 and CD14 are dispensable for the acute response at the injury site but differentially regulate microglial and neuronal activation in remote brain regions, representing potential targets to reduce P-TBI-associated encephalopathy.

MeSH

Cytokines, Hippocampus, Microglia, Brain, Multiple Trauma, Wounds And Injuries, Dependency, Psychological