Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury
Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury
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DOI：
10.1152/ajprenal.00461.2007
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发表时间：
2008-05-01
影响因子：
4.2
通讯作者：
Star, Robert A.
中科院分区：
文献类型：
--
作者：
Yasuda, Hideo;Leelahavanichkul, Asada;Star, Robert A.
尽管最近在支持性和靶向治疗方面取得了进展，但败血症的死亡率仍然很高。 Toll 样受体 (TLR) 感知细菌产物并刺激致病性先天免疫反应。缺乏大多数 TLR 下游的常见接头蛋白 MyD88 的小鼠可以降低多种微生物败血症引起的死亡率和急性肾损伤 (AKI)。然而，负责宿主对多种微生物败血症反应的 TLR 的身份尚不清楚。在这里，我们表明，氯喹是一种内吞性 TLR（TLR3、7、8、9）抑制剂，可改善临床相关的多微生物脓毒症小鼠模型中脓毒症引起的死亡率和 AKI，即使在脓毒症损伤后 6 小时给药也是如此。氯喹给药减轻了肾功能、脾细胞凋亡、其他器官损伤的血清标志物以及典型血清促炎和抗炎细胞因子 TNF-α 和 IL-10 的下降。 TLR9 和 TLR9 缺陷小鼠的寡脱氧核苷酸抑制剂 (H154) 在我们测试的所有功能参数中反映了氯喹的作用。此外，氯喹降低了脾脏中 TLR9 蛋白的丰度，进一步表明 TLR9 信号传导可能是氯喹保护作用的主要目标。我们的研究结果表明，氯喹通过抑制导致多种微生物败血症的多种途径来提高生存率，氯喹和 TLR9 抑制剂分别代表可行的广谱和靶向治疗策略，是进一步临床开发的有希望的候选者。
Mortality from sepsis has remained high despite recent advances in supportive and targeted therapies. Toll-like receptors (TLRs) sense bacterial products and stimulate pathogenic innate immune responses. Mice deficient in the common adapter protein MyD88, downstream from most TLRs, have reduced mortality and acute kidney injury (AKI) from polymicrobial sepsis. However, the identity of the TLR(s) responsible for the host response to polymicrobial sepsis is unknown. Here, we show that chloroquine, an inhibitor of endocytic TLRs (TLR3, 7, 8, 9), improves sepsis-induced mortality and AKI in a clinically relevant polymicrobial sepsis mouse model, even when administered 6 h after the septic insult. Chloroquine administration attenuated the decline in renal function, splenic apoptosis, serum markers of damage to other organs, and prototypical serum pro- and anti-inflammatory cytokines TNF-alpha and IL-10. An oligodeoxynucleotide inhibitor (H154) of TLR9 and TLR9-deficient mice mirror the actions of chloroquine in all functional parameters that we tested. In addition, chloroquine decreased TLR9 protein abundance in spleen, further suggesting that TLR9 signaling may be a major target for the protective actions of chloroquine. Our findings indicate that chloroquine improves survival by inhibiting multiple pathways leading to polymicrobial sepsis and that chloroquine and TLR9 inhibitors represent viable broad-spectrum and targeted therapeutic strategies, respectively, that are promising candidates for further clinical development.