{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T09:23:06Z","timestamp":1788340986191,"version":"build-2803163510"},"reference-count":70,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2023YFC3402600"],"award-info":[{"award-number":["2023YFC3402600"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Basic Research Program of China","doi-asserted-by":"publisher","award":["2021YFA1101801"],"award-info":[{"award-number":["2021YFA1101801"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014219","name":"National Science Fund for Distinguished Young Scholars","doi-asserted-by":"publisher","award":["32325025"],"award-info":[{"award-number":["32325025"]}],"id":[{"id":"10.13039\/501100014219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuroprotection"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Traumatic brain injury (TBI) involves complex secondary injury cascades in which neuroinflammation is a prominent driver. The lack of standardized models capturing a spectrum of injury severities has hindered a systematic understanding of the associated cellular and molecular responses. This study aims to systematically characterize the dynamic responses and phenotypic shifts of neurons, microglia, and astrocytes during the acute and subacute phases following TBI of varying severities. By integrating macroscopic histopathological assessments with microscopic cellular analyses and correlating these with early peripheral biomarker changes, we seek to provide a solid experimental foundation for understanding TBI mechanisms and developing severity\u2010stratified diagnostic and therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Male mice were randomly assigned using a computer\u2010generated randomization sequence to the following experimental groups: Sham group, mice that underwent only craniotomy (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200910 per group); Mild group, mice with a 0.5\u2009mm depth impact on the right motor cortex (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200910 per group); Moderate group, mice with a 1.0\u2009mm depth impact on the right motor cortex (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200910 per group); Severe group, mice with a 2.0\u2009mm depth impact on the right motor cortex (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200910 per group). On Days 1, 3, 7, and 14 after injury, tissue damage was assessed using Nissl staining; anxiety\u2010like behavior was evaluated using the elevated plus maze; cognitive function was assessed using the Y\u2010maze test; motor function was evaluated using the open field test, balance beam test, rotarod test, and gait analysis; neuronal apoptosis and glial cell polarization levels were assessed using immunofluorescence staining; and changes in peripheral serum markers were measured using enzyme\u2010linked immunosorbent assay (Elisa). In addition, severely injured mice received minocycline treatment (45\u2009mg\/kg,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200912 per group) from 30\u2009min to Day 3 post\u2010injury, while the control group received the same volume of saline. For comparisons between groups at a single time point, one\u2010way analysis of variance (ANOVA) followed by Tukey's multiple comparisons test was used. For comparisons between groups across multiple time points, two\u2010way ANOVA followed by Tukey's multiple comparisons test was applied.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Impact depth was directly correlated with histopathological lesion volume and dictated the trajectory of functional recovery. Motor deficits and neuronal apoptosis scaled with injury severity. The neuroimmune response was severity\u2010dependent: mild TBI triggered a transient, reparative response dominated by M2 microglia and A2 astrocytes. In contrast, severe TBI provoked an early and sustained pro\u2010inflammatory state, characterized by persistent M1 microglial and neurotoxic A1 astrocytic activation (\n                      <jats:italic>n\u2009<\/jats:italic>\n                      =\u20094 per group,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). Furthermore, severe injury led to significant acute elevations in serum interleukin\u20106 (IL\u20106) and ubiquitin carboxy\u2010terminal hydrolase L1 (UCHL1) within 6\u2009h post\u2010injury (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093 per group,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001). Minocycline treatment attenuated neuroinflammation, improved motor function, and promoted a shift in microglial polarization toward the protective M2 phenotype (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009&gt;\u20094 per group, all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings establish that TBI severity is a critical determinant of the post\u2010injury neuroimmune microenvironment, with severe injuries driving a maladaptive, chronic inflammatory response. This graded model provides a robust framework for identifying severity\u2010specific biomarkers and validates the rationale for developing precision immunomodulatory therapies stratified by injury severity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/nep3.70044","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T06:38:07Z","timestamp":1784529487000},"page":"275-294","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Graded traumatic brain injury severity differentially modulates microglial and astrocytic polarization states and response to minocycline"],"prefix":"10.1002","volume":"4","author":[{"given":"Yan","family":"Yu","sequence":"first","affiliation":[{"name":"School of Basic Medicine Qingdao University Qingdao Shandong 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