Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia Division, Boston Children's Hospital, Boston, Massachusetts, USA.
Department of Anaesthesia and Immunology, Harvard Medical School, Boston, Massachusetts, USA.
FASEB J. 2022 Aug;36(8):e22481. doi: 10.1096/fj.202200312R.
Sedatives/anesthetics are important medical tools to facilitate medical care and increase patients' comfort. Increasingly, there is recognition that sedatives/anesthetics can modulate immune functions. Toll-like receptors (TLRs) are major pattern recognition receptors involved in the recognition of microbial components. TLR7 recognizes single-strand RNA virus such as influenza and SARS-CoV2 viruses and initiates interferon (IFN) responses. IFN production triggered by TLR7 stimulation is a critical anti-viral response. For example, patients with TLR7 variants including loss-of- function variants were associated with severe COVID-19. Taken together, it is important to determine if sedatives/anesthetics mitigate TLR7 function. We have previously showed that TLR7-mediated activation was not affected by volatile anesthetics. However, we found that propofol attenuated TLR7 activation among intravenous sedatives in the reporter assay. TLR7 agonist R837 stimulation increased TNF-α, IL-1β, IL-6, IL-10, and IFN-β mRNA levels in bone marrow-derived dendritic cells, while these levels were attenuated by propofol. Our murine lung slice experiments showed that propofol attenuated IFN production. R837 increased IFN-β expression in the lungs, and propofol attenuated IFN-β expression in an in vivo model of R837 intranasal instillation. We also found that propofol directly bound to and hindered its association of TLR7 with MyD88. Our analysis using fropofol, propofol derivative showed that the hydroxyl group in propofol was important for propofol-TLR7 interaction.
镇静剂/麻醉剂是促进医疗护理和提高患者舒适度的重要医学工具。越来越多的人认识到，镇静剂/麻醉剂可以调节免疫功能。Toll 样受体 (TLR) 是参与识别微生物成分的主要模式识别受体。TLR7 识别单链 RNA 病毒，如流感病毒和 SARS-CoV2 病毒，并启动干扰素 (IFN) 反应。TLR7 刺激引发的 IFN 产生是一种关键的抗病毒反应。例如，携带 TLR7 变异体（包括功能丧失变异体）的患者与严重的 COVID-19 相关。综上所述，确定镇静剂/麻醉剂是否减轻 TLR7 功能非常重要。我们之前曾表明，挥发性麻醉剂不会影响 TLR7 介导的激活。然而，我们发现丙泊酚在报告基因检测中减弱了静脉内镇静剂对 TLR7 的激活。TLR7 激动剂 R837 刺激可增加骨髓来源树突状细胞中 TNF-α、IL-1β、IL-6、IL-10 和 IFN-βmRNA 水平，而丙泊酚则减弱了这些水平。我们的鼠肺切片实验表明，丙泊酚可抑制 IFN 的产生。R837 增加了肺部 IFN-β 的表达，而丙泊酚在 R837 鼻腔内滴注的体内模型中减弱了 IFN-β 的表达。我们还发现丙泊酚直接与 TLR7 结合并阻碍其与 MyD88 的结合。我们使用丙泊酚衍生物的分析表明，丙泊酚中的羟基对丙泊酚-TLR7 相互作用很重要。
