TLR4 mediates post-traumatic depression via kynurenine pathway activation in a murine traumatic brain injury model

Introduction: 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. Methods and Results: : LPS-stimulated BV2 microglia showed increased IDO1/KMO/QUIN expression, which was abolished by TAK-242 pretreatment. Conclusion: Our findings establish a novel TLR4-KP-QUIN 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.