Interleukin-23 Secreted by Activated Macrophages Drives gamma delta T Cell Production of Interleukin-17 to Aggravate Secondary Injury After Intracerebral Hemorrhage
Interleukin-23 Secreted by Activated Macrophages Drives gamma delta T Cell Production of Interleukin-17 to Aggravate Secondary Injury After Intracerebral Hemorrhage
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活化巨噬细胞分泌的白细胞介素23驱动γδT细胞产生白细胞介素17，加重脑出血后的继发性损伤
DOI：
10.1161/jaha.116.004340
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发表时间：
2016
影响因子：
5.4
通讯作者：
Yang Qing-Wu
中科院分区：
文献类型：
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作者：
Zhong Qi;Zhou Kai;Liang Qiao-Li;Lin Sen;Wang Yan-Chun;Xiong Xiao-Yi;Meng Zhao-You;Zhao Ting;Zhu Wen-Yao;Yang Yuan-Rui;Liao Mao-Fan;Gong Qiu-Wen;Liu Liang;Xiong Ao;Hao Junwei;Wang Jian;Yang Qing-Wu
背景神经炎症在脑出血（ICH）引起的继发性脑损伤中起关键作用，但巨噬细胞和淋巴细胞等外周炎症细胞的具体作用仍不清楚。本研究的目的是探讨巨噬细胞、T 淋巴细胞及其分泌的细胞因子作为治疗 ICH 后继发性脑损伤的潜在靶标的作用。方法和结果我们的结果显示，外周巨噬细胞和 T 淋巴细胞相继浸润大脑，巨噬细胞计数在 ICH 后 1 天达到峰值，T 淋巴细胞计数在 4 天后达到峰值。细胞浸润的这些峰值分别对应于白细胞介素 (IL)-23 和 IL-17 表达的增加。我们发现血肿中的血红蛋白通过诱导 Toll 样受体 (TLR) 2/4 异二聚体的形成，通过浸润巨噬细胞激活 IL-23 分泌。 IL-23 表达的增加刺激了 γδT 细胞产生 IL-17，作为促炎因子，IL-17 增加了模型小鼠的脑水肿和神经功能缺损。最后，我们发现 sparstolonin B (SsnB) 可以通过抑制 TLR2/TLR4 异二聚体形成来改善 ICH 模型小鼠的脑水肿和神经功能缺损，值得注意的是，SsnB 与骨髓分化因子 88 Arg196 相互作用。 结论 总之，我们的结果揭示了 IL-23/IL-17 炎症轴在 ICH后继发性脑损伤，为ICH治疗提供新的治疗靶点。
BackgroundNeuroinflammation plays a key role in intracerebral hemorrhage (ICH)–induced secondary brain injury, but the specific roles of peripheral inflammatory cells such as macrophages and lymphocytes remain unknown. The purpose of this study was to explore the roles of macrophages, T lymphocytes, and the cytokines they secrete as potential targets for treating secondary brain injury after ICH.Methods and ResultsOur results showed that peripheral macrophages and T lymphocytes successively infiltrated the brain, with macrophage counts peaking 1 day after ICH and T‐lymphocyte counts peaking after 4 days. These peaks in cellular infiltration corresponded to increases in interleukin (IL)‐23 and IL‐17 expression, respectively. We found that hemoglobin from the hematoma activated IL‐23 secretion by infiltrating macrophages by inducing the formation of toll‐like receptor (TLR) 2/4 heterodimer. This increased IL‐23 expression stimulated γδT‐cell production of IL‐17, which increased brain edema and neurologic deficits in the model mice as a proinflammatory factor. Finally, we found that sparstolonin B (SsnB) could ameliorate brain edema and neurologic deficits in ICH model mice via inhibition of TLR2/TLR4 heterodimer formation, and notably, SsnB interacted with myeloid differentiation factor 88 Arg196.ConclusionsTogether, our results reveal the importance of the IL‐23/IL‐17 inflammatory axis in secondary brain injury after ICH and thus provide a new therapeutic target for ICH treatment.