{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:57:42Z","timestamp":1792652262950,"version":"4.5.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Traumatic brain injury (TBI) triggers a cascade of neuroinflammatory responses mediated by microglial activation, which significantly contributes to secondary brain damage. While triggering receptor expressed on myeloid cells-1 (TREM-1) is a key inflammatory amplifier, its mechanistic role and therapeutic potential in TBI remain elusive. Thus, this study endeavored to elucidate the exact role of TREM-1 in experimental TBI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A controlled cortical impact (CCI) model was established in male C57BL\/6 mice to induce TBI. The temporal expression profile of TREM-1 was assessed using RNA sequencing and Western blot (WB). The TREM-1 inhibitory peptide LP17 was administered intranasally at 2 hours post-injury (hpi). Neurobehavioral assessments, histological analyses, immunofluorescence (IF), brain water content (BWC) measurement, Evans blue (EB) assays and laser speckle contrast imaging (LSCI) were performed in this study.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments using BV2 microglial cells were conducted to investigate the molecular mechanisms underlying TREM-1-mediated inflammation. Spleen tyrosine kinase (SYK) inhibition was achieved using R406, and TREM-1 small interfering RNA (siRNA) and overexpressing plasmids were performed to validate its role in NF-\u03baB signaling and pyroptosis quantified using WB and enzyme-linked immunosorbent assay (ELISA). Quantitative data are expressed as mean \u00b1 SD, and group comparisons were made by two-tailed Student\u2019s t-tests or one-way ANOVA with Tukey\u2019s\n                      <jats:italic>post hoc<\/jats:italic>\n                      test, with\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05 considered statistically significant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TBI significantly upregulated TREM-1 expression in microglia, peaking at 3 days post-injury (dpi). Intranasal administration of the TREM-1 antagonist LP17 treatment attenuated neuroinflammation, reduced blood-brain barrier disruption, ameliorated cerebral blood flow decrease, promoted synaptic remodeling, and improved functional outcomes. Mechanistically, through its interaction with SYK, TREM-1 triggered the CARD9\/NF-\u03baB signaling and induced pyroptosis. SYK inhibition reversed these effects, confirming the necessity of the TREM-1\/SYK axis in neuroinflammatory signaling.\n                      <jats:italic>In vitro<\/jats:italic>\n                      studies further demonstrated that TREM-1 overexpression enhanced SYK phosphorylation, NF-\u03baB activation, and pyroptosis, while LP17 or R406 treatment suppressed these responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our finding demonstrates that TREM-1 critically mediates neuroinflammation and synaptic dysfunction after TBI. Pharmacological targeting of TREM-1 attenuates neuroinflammation, reduces cerebral edema, preserves blood-brain barrier integrity, and improves functional recovery. These effects are mediated through suppression of TREM-1-dependent NF-\u03baB signaling and pyroptosis. These results highlight TREM-1 as a promising therapeutic target for TBI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1636917","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T04:10:43Z","timestamp":1753071043000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["TREM-1 as a potential gatekeeper of neuroinflammatory responses: therapeutic validation and mechanistic insights in experimental traumatic brain 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