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 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 days 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 21–28 post-TBI) ameliorated depressive behaviors and suppressed phosphorylation of NF-κB 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 in vitro : 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.
Li et al. (Wed,) studied this question.