DAMP Signaling is a Key Pathway Inducing Immune Modulation after Brain Injury
DAMP Signaling is a Key Pathway Inducing Immune Modulation after Brain Injury
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DOI：
10.1523/jneurosci.2439-14.2015
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发表时间：
2015-01-14
影响因子：
5.3
通讯作者：
Veltkamp, Roland
中科院分区：
文献类型：
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作者：
Liesz, Arthur;Dalpke, Alexander;Veltkamp, Roland
急性脑损伤导致外周免疫反应的深刻变化，包括早期免疫激活和随后的免疫抑制的相反现象。这种大脑免疫信号背后的机制在很大程度上是未知的。我们使用实验性脑缺血的动物模型作为急性脑损伤的范例，并另外调查了大量中风患者。我们用质谱仪分析了HMGB1异构体的释放，并用体内和体外免疫学技术研究了其炎症效力和信号转导途径。对复杂的行为病态行为综合征的特征进行了家庭行为分析。HMGB1下游信号，特别是与RAGE的信号，在各种转基因动物模型中和通过药物阻断进行了研究。我们的结果表明，在卒中超急性期，细胞因子诱导的、完全还原的HMGB1亚型从小鼠和患者的缺血脑中释放出来。外周分泌的细胞因子对脑损伤引起的疾病行为作出反应，可通过抑制HMGB1-RAGE通路或直接中和细胞因子而被取消。随后，HMGB1释放诱导骨髓源性抑制细胞的骨髓外逃和脾细胞增殖，抑制体内和体外的获得性免疫反应。此外，HMGB1-RAGE信号导致成熟单核细胞功能衰竭和淋巴细胞减少，这是广泛缺血后免疫抑制的特征。本研究介绍了HMGB1-RAGE介导的通路作为解释复杂的脑缺血后免疫相互作用的关键机制。
Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We analyzed release of HMGB1 isoforms by mass spectrometry and investigated its inflammatory potency and signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, was studied in various transgenic animal models and by pharmacological blockade. Our results indicate that the cytokine-inducing, fully reduced isoform of HMGB1 was released from the ischemic brain in the hyperacute phase of stroke in mice and patients. Cytokines secreted in the periphery in response to brain injury induced sickness behavior, which could be abrogated by inhibition of the HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release induced bone marrow egress and splenic proliferation of bone marrow-derived suppressor cells, inhibiting the adaptive immune responses in vivo and vitro. Furthermore, HMGB1-RAGE signaling resulted in functional exhaustion of mature monocytes and lymphopenia, the hallmarks of immune suppression after extensive ischemia. This study introduces the HMGB1-RAGE-mediated pathway as a key mechanism explaining the complex postischemic brain-immune interactions.