{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T09:56:16Z","timestamp":1785232576781,"version":"3.55.0"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Traumatic brain injury (TBI) is a major risk factor for major depressive disorder (MDD), yet the underlying mechanisms remain poorly defined. This study demonstrates that toll-like receptor 4 (TLR4) activation drives depressive-like behaviors through dysregulation of the kynurenine pathway (KP) in a murine model of moderate TBI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>\n                      Using male C57BL\/6J mice subjected to controlled cortical impact, we observed depression-like phenotypes (reduced sucrose preference, prolonged immobility in forced swimming tests) specifically at 28\u00a0days post-TBI, with an incidence of 28.13%. Proteomics and immunofluorescence analyses revealed significant upregulation of hippocampal TLR4 expression and signaling pathway activation, concomitant with microglial activation. Crucially, the TLR4-specific inhibitor TAK-242 (administered i.p. from days 21\u201328 post-TBI) ameliorated depressive behaviors and suppressed phosphorylation of NF-\u03baB p65. Mechanistically, TBI induced microglia-dependent upregulation of key KP enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine monooxygenase (KMO), leading to accumulation of the neurotoxic metabolite quinolinic acid (QUIN). This TLR4-KP axis was validated\n                      <jats:italic>in vitro<\/jats:italic>\n                      : LPS-stimulated BV2 microglia showed increased IDO1\/KMO\/QUIN expression, which was abolished by TAK-242 pretreatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings establish a novel TLR4\u2013KP\u2013QUIN pathway as a critical mediator of post-TBI depression, providing a mechanistic basis for TLR4-targeted therapies. In addition to neuroinflammatory effects, this work mainly mediates dysregulation of TBI-related neuropsychiatric sequelae through metabolism, highlighting TLR4 inhibition as a promising strategy for mitigating chronic depressive outcomes after brain injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1744031","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T06:31:28Z","timestamp":1776234688000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["TLR4 mediates post-traumatic depression via kynurenine pathway activation in a murine traumatic brain injury model"],"prefix":"10.3389","volume":"17","author":[{"given":"Chang-Hong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Anatomy, Anhui Medical University","place":["Hefei, Anhui, China"]},{"name":"The Molecular Biology Center, State Key Laboratory of Trauma and Chemical Poisoning, Department of Army Occupational Disease, Daping Hospital, Army Medical University (Third Military Medical University)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"The Molecular Biology Center, State Key Laboratory of Trauma and Chemical Poisoning, Department of Army Occupational Disease, Daping Hospital, Army Medical University (Third Military Medical University)","place":["Chongqing, China"]},{"name":"Center of Bone Metabolism and repair, Laboratory for Prevention and Rehabilitation of Training injuries, State Key Laboratory of Trauma and Chemical Poisoning, Trauma center, Research Institute of Surgery, Daping Hospital, Army Medical University (Third Military Medical University)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruo-Bing","family":"Gao","sequence":"additional","affiliation":[{"name":"The Molecular Biology Center, State Key Laboratory of Trauma and Chemical Poisoning, Department of Army Occupational Disease, Daping Hospital, Army Medical University (Third Military Medical University)","place":["Chongqing, China"]},{"name":"Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Peng","sequence":"additional","affiliation":[{"name":"The Molecular Biology Center, State Key Laboratory of Trauma and Chemical Poisoning, Department of Army Occupational Disease, Daping Hospital, Army Medical University (Third Military Medical University)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"The Molecular Biology Center, State Key Laboratory of Trauma and Chemical Poisoning, Department of Army Occupational Disease, Daping Hospital, Army Medical University (Third Military Medical University)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1007\/s12035-018-1184-8","article-title":"Inhibition of toll-like Receptor-4 (TLR-4) improves neurobehavioral outcomes after acute ischemic stroke in diabetic rats: possible role of vascular endothelial TLR-4","volume":"56","author":"Abdul","year":"2019","journal-title":"Mol. 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