{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:06:54Z","timestamp":1788880014053,"version":"build-2803163510"},"reference-count":83,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":250,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82174483"],"award-info":[{"award-number":["82174483"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A1515012169"],"award-info":[{"award-number":["2024A1515012169"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pain Research and Management"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Pain following traumatic brain injury (TBI) is a major challenge in clinical management. Neuroinflammatory responses, particularly those involving microglia, are increasingly implicated in the synaptic and circuit\u2010level remodeling associated with post\u2010TBI pain. However, the conventional M1\/M2 framework does not adequately capture the temporal and functional diversity of microglial states after injury. This study aimed to characterize microglial heterogeneity and identify specific microglial subpopulations potentially associated with post\u2010TBI pain\u2013related neural remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We reanalyzed the publicly available single\u2010cell RNA sequencing dataset GSE226207, which comprised intact cortical samples and cortical samples collected at 3 and 5\u2009days after cortical stab\u2010wound injury from control and inhibitor\u2010treated mice. The inhibitor\u2010treated groups received combined pharmacological inhibition of the CXCR3 and TLR1\/2 pathways. Seurat was used for data processing, clustering, cell\u2010type annotation, and microglial subclustering. AUCell was applied to evaluate inflammatory\u2010, repair\u2010, and pain\u2010relevant gene signatures. CytoTRACE and Slingshot were used to assess relative transcriptional complexity and infer state\u2010transition trajectories. CellChat analysis of pooled cells from all groups was performed to predict intercellular communication, and SCENIC was used to characterize subpopulation\u2010associated regulon activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 66,310\u2009cells were retained, including 7648 microglia that were resolved into eight transcriptionally distinct subpopulations. Among them, the\n                      <jats:italic>L<\/jats:italic>\n                      <jats:italic>a<\/jats:italic>\n                      <jats:italic>r<\/jats:italic>\n                      <jats:italic>s<\/jats:italic>\n                      2\n                      <jats:sup>+<\/jats:sup>\n                      microglial subpopulation showed lower representation in the 3\u2009days postinjury (dpi) groups and greater representation in the 5 dpi groups. This subpopulation exhibited relatively high TGF\u2010\u03b2\u2013 and MAPK\u2010associated signature scores and was enriched in biological processes related to synaptic organization, axonogenesis, dendrite development, and protein synthesis. Slingshot positioned\n                      <jats:italic>L<\/jats:italic>\n                      <jats:italic>a<\/jats:italic>\n                      <jats:italic>r<\/jats:italic>\n                      <jats:italic>s<\/jats:italic>\n                      2\n                      <jats:sup>+<\/jats:sup>\n                      microglia at the distal end of one inferred state\u2010transition lineage. CellChat analysis predicted prominent neuron\u2010to\u2010microglia communication through the CX3CL1\u2013CX3CR1 ligand\u2013receptor pair, with\n                      <jats:italic>L<\/jats:italic>\n                      <jats:italic>a<\/jats:italic>\n                      <jats:italic>r<\/jats:italic>\n                      <jats:italic>s<\/jats:italic>\n                      2\n                      <jats:sup>+<\/jats:sup>\n                      microglia predominantly positioned as signal receivers. SCENIC further identified relatively high activity of regulatory module M1 in\n                      <jats:italic>L<\/jats:italic>\n                      <jats:italic>a<\/jats:italic>\n                      <jats:italic>r<\/jats:italic>\n                      <jats:italic>s<\/jats:italic>\n                      2\n                      <jats:sup>+<\/jats:sup>\n                      microglia, with\n                      <jats:italic>Thra<\/jats:italic>\n                      among the highly ranked regulators.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study identifies the\n                      <jats:italic>L<\/jats:italic>\n                      <jats:italic>a<\/jats:italic>\n                      <jats:italic>r<\/jats:italic>\n                      <jats:italic>s<\/jats:italic>\n                      2\n                      <jats:sup>+<\/jats:sup>\n                      microglial subpopulation as a temporally dynamic and transcriptionally specialized component of the postinjury microglial landscape. The convergence of pain\u2010relevant signaling signatures, neural remodeling programs, inferred state\u2010transition characteristics, predicted neuron\u2013microglia communication involving the CX3CL1\u2013CX3CR1 pair, and\n                      <jats:italic>Thra<\/jats:italic>\n                      \u2010associated regulon activity supports a potential role for\n                      <jats:italic>L<\/jats:italic>\n                      <jats:italic>a<\/jats:italic>\n                      <jats:italic>r<\/jats:italic>\n                      <jats:italic>s<\/jats:italic>\n                      2\n                      <jats:sup>+<\/jats:sup>\n                      microglia in posttraumatic neuroimmune and synaptic remodeling. These findings provide a cellular and molecular framework for future investigation of microglia\u2010targeted strategies for post\u2010TBI pain.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/prm\/2444554","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:12:07Z","timestamp":1788876727000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dissection of Microglial Heterogeneity and Identification of Pain\u2010Related Subpopulations After Traumatic Brain Injury"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7226-3730","authenticated-orcid":false,"given":"Fu","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8708-6553","authenticated-orcid":false,"given":"Jingru","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7295-0783","authenticated-orcid":false,"given":"Yimin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7647-8718","authenticated-orcid":false,"given":"Luxi","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"e_1_2_13_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(22)00309-x"},{"key":"e_1_2_13_2_2","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S1474-4422(18)30415-0","article-title":"Global, Regional, and National Burden of Traumatic Brain Injury and Spinal Cord Injury, 1990-2016: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Gbd T. B. I. A.","year":"2019","journal-title":"The Lancet. Neurology"},{"key":"e_1_2_13_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apmr.2010.05.017"},{"key":"e_1_2_13_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2023.105630"},{"key":"e_1_2_13_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pmr.2024.02.009"},{"key":"e_1_2_13_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fresc.2024.1398856"},{"key":"e_1_2_13_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pmr.2025.07.003"},{"key":"e_1_2_13_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2024.01.084"},{"key":"e_1_2_13_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2017.13"},{"key":"e_1_2_13_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-20292-7"},{"key":"e_1_2_13_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.08.018"},{"key":"e_1_2_13_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2017.00208"},{"key":"e_1_2_13_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-024-01897-x"},{"key":"e_1_2_13_14_2","doi-asserted-by":"publisher","DOI":"10.4103\/nrr.nrr-d-25-00902"},{"key":"e_1_2_13_15_2","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.2469-20.2020"},{"key":"e_1_2_13_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46625-w"},{"key":"e_1_2_13_17_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1584577"},{"key":"e_1_2_13_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.10.020"},{"key":"e_1_2_13_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.018"},{"key":"e_1_2_13_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.039"},{"key":"e_1_2_13_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.11.004"},{"key":"e_1_2_13_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-10419-1"},{"key":"e_1_2_13_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00307"},{"key":"e_1_2_13_24_2","doi-asserted-by":"publisher","DOI":"10.15212\/bioi-2025-0159"},{"key":"e_1_2_13_25_2","doi-asserted-by":"publisher","DOI":"10.34133\/research.0901"},{"key":"e_1_2_13_26_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1584350"},{"key":"e_1_2_13_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_2_13_28_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-011036"},{"key":"e_1_2_13_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1569988"},{"key":"e_1_2_13_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2019.03.003"},{"key":"e_1_2_13_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e37726"},{"key":"e_1_2_13_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1552"},{"key":"e_1_2_13_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"e_1_2_13_34_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-008759"},{"key":"e_1_2_13_35_2","article-title":"Single\u2010Cell Transcriptomic Analysis of the Immune Response to COVID\u201019 and Tuberculosis Coinfection","volume":"8","author":"Wang Y.","year":"2025","journal-title":"Exploration"},{"key":"e_1_2_13_36_2","doi-asserted-by":"publisher","DOI":"10.34133\/research.0690"},{"key":"e_1_2_13_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s43657-023-00133-x"},{"key":"e_1_2_13_38_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-004206"},{"key":"e_1_2_13_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/mdr2.70010"},{"key":"e_1_2_13_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202506476"},{"key":"e_1_2_13_41_2","doi-asserted-by":"publisher","DOI":"10.15212\/cvia.2023.0023"},{"key":"e_1_2_13_42_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax0249"},{"key":"e_1_2_13_43_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-4772-0"},{"key":"e_1_2_13_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2025.07.047"},{"key":"e_1_2_13_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21246-9"},{"key":"e_1_2_13_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/exp.20220171"},{"key":"e_1_2_13_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2023.06.007"},{"key":"e_1_2_13_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2023.11.020"},{"key":"e_1_2_13_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"e_1_2_13_50_2","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnx153"},{"key":"e_1_2_13_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbih.2024.100723"},{"key":"e_1_2_13_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.07.010"},{"key":"e_1_2_13_53_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02197-w"},{"key":"e_1_2_13_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.03.020"},{"key":"e_1_2_13_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2015.04.029"},{"key":"e_1_2_13_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4397"},{"key":"e_1_2_13_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3599"},{"key":"e_1_2_13_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.10286"},{"key":"e_1_2_13_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep11252"},{"key":"e_1_2_13_60_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200425430"},{"key":"e_1_2_13_61_2","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.2396-04.2004"},{"key":"e_1_2_13_62_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2003.01969.x"},{"key":"e_1_2_13_63_2","doi-asserted-by":"publisher","DOI":"10.1097\/aln.0000000000002130"},{"key":"e_1_2_13_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2016.162"},{"key":"e_1_2_13_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.03.026"},{"key":"e_1_2_13_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2018.2"},{"key":"e_1_2_13_67_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-023-01616-y"},{"key":"e_1_2_13_68_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12017-021-08700-z"},{"key":"e_1_2_13_69_2","doi-asserted-by":"crossref","first-page":"705","DOI":"10.4103\/1673-5374.322423","article-title":"Microglia Regulation of Synaptic Plasticity and Learning and Memory","volume":"17","author":"Cornell J.","year":"2022","journal-title":"Neural Regeneration Research"},{"key":"e_1_2_13_70_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9102277"},{"key":"e_1_2_13_71_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-015-0386-5"},{"key":"e_1_2_13_72_2","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/4637073"},{"key":"e_1_2_13_73_2","doi-asserted-by":"publisher","DOI":"10.3389\/fpain.2021.684684"},{"key":"e_1_2_13_74_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1908762116"},{"key":"e_1_2_13_75_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncpendmet0424"},{"key":"e_1_2_13_76_2","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.21-06-02028.2001"},{"key":"e_1_2_13_77_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22792"},{"key":"e_1_2_13_78_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38798-7"},{"key":"e_1_2_13_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2021.08.210"},{"key":"e_1_2_13_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.115717"},{"key":"e_1_2_13_81_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065479"},{"key":"e_1_2_13_82_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-022-00970-3"},{"key":"e_1_2_13_83_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23883"}],"container-title":["Pain Research and Management"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/prm\/2444554","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/prm\/2444554","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/prm\/2444554","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:12:09Z","timestamp":1788876729000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/prm\/2444554"}},"subtitle":[],"editor":[{"given":"Lei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":83,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1155\/prm\/2444554"],"URL":"https:\/\/doi.org\/10.1155\/prm\/2444554","archive":["Portico"],"relation":{},"ISSN":["1203-6765","1918-1523"],"issn-type":[{"value":"1203-6765","type":"print"},{"value":"1918-1523","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2026-06-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2444554"}}