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Res."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      P-TBI induced a rapid, brain-wide increase in inflammatory cytokines with region-specific patterns.\n                      <jats:italic>TNF<\/jats:italic>\n                      and\n                      <jats:italic>CCL2<\/jats:italic>\n                      mRNA were upregulated in microglia in the cortex, hippocampus, and striatum, and this response was abolished in\n                      <jats:italic>C3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>CD14<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      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\n                      <jats:italic>cFOS<\/jats:italic>\n                      responses showed an inverse regional C3\/CD14 dependency compared with inflammatory cytokine responses, with a cortical C3 dependency and striatal CD14 dependency.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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\u2013associated encephalopathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00011-026-02367-7","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:09:07Z","timestamp":1790276947000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of C3 and CD14 reduces region-specific neuroinflammation in a murine polytrauma model"],"prefix":"10.1007","volume":"75","author":[{"given":"Florian","family":"Olde Heuvel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marica","family":"Pagliarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludmila","family":"Lupu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongren","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Likun","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Halbgebauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Mannes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias Maria","family":"Boeckers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Kn\u00f6ll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Egil","family":"Lien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom Eirik","family":"Mollnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Huber-Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Roselli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"2367_CR1","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1097\/TA.0000000000000453","volume":"77","author":"HC Pape","year":"2014","unstructured":"Pape HC, Lefering R, Butcher N, Peitzman A, Leenen L, Marzi I, et al. 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