Brain, behavior, and immunity · 2026
Injury-environment interaction: microglial priming by mTBI creates vulnerability to subsequent stress via the HMGB1-RAGE axis.
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Qiu Jing, Yang Guang, Cai Jingling, Chen Chen, Liang Shiting, Huang Haohao, Ma Lianting
Аннотация
BACKGROUND: The mechanisms underlying the increased risk of depression following mild traumatic brain injury (mTBI) remain poorly understood, particularly the synergistic interaction between the initial injury and subsequent environmental stress. This study aims to elucidate the molecular cascade governing this "injury-stress" synergy.
METHODS: We developed a "two-hit" mouse model combining mTBI with chronic unpredictable mild stress (CUMS) to investigate their interaction. Our approach integrated behavioral testing with molecular, immunohistochemical, and targeted genetic manipulations (AAV-mediated) in the medial prefrontal cortex (mPFC) to establish causal links.
RESULTS: We found that mTBI alone did not induce significant behavioral deficits but instead established a state of latent vulnerability by driving persistent microglial priming in the mPFC. Sustained release of High-Mobility Group Box 1 (HMGB1) post-mTBI was identified as the key driver of this priming. Mechanistically, we demonstrate that chronic stress did not act by further increasing HMGB1 levels, but by amplifying downstream signaling efficiency through the selective upregulation of its receptor, RAGE. Bidirectional genetic interventions confirmed that RAGE is the critical molecular switch that translates the "second-hit" of stress into pathological amplification, culminating in exacerbated neuroinflammation, synaptic loss, and severe behavioral deficits.
CONCLUSION: Our study untangles a "priming-triggering" mechanism of injury-environment interaction, identifying the HMGB1-RAGE axis as its key molecular mediator. This finding not only enhances our understanding of how latent vulnerability transitions into overt neuropsychiatric disease, but also provides a promising target for preventive intervention.
METHODS: We developed a "two-hit" mouse model combining mTBI with chronic unpredictable mild stress (CUMS) to investigate their interaction. Our approach integrated behavioral testing with molecular, immunohistochemical, and targeted genetic manipulations (AAV-mediated) in the medial prefrontal cortex (mPFC) to establish causal links.
RESULTS: We found that mTBI alone did not induce significant behavioral deficits but instead established a state of latent vulnerability by driving persistent microglial priming in the mPFC. Sustained release of High-Mobility Group Box 1 (HMGB1) post-mTBI was identified as the key driver of this priming. Mechanistically, we demonstrate that chronic stress did not act by further increasing HMGB1 levels, but by amplifying downstream signaling efficiency through the selective upregulation of its receptor, RAGE. Bidirectional genetic interventions confirmed that RAGE is the critical molecular switch that translates the "second-hit" of stress into pathological amplification, culminating in exacerbated neuroinflammation, synaptic loss, and severe behavioral deficits.
CONCLUSION: Our study untangles a "priming-triggering" mechanism of injury-environment interaction, identifying the HMGB1-RAGE axis as its key molecular mediator. This finding not only enhances our understanding of how latent vulnerability transitions into overt neuropsychiatric disease, but also provides a promising target for preventive intervention.