期刊
FASEB JOURNAL
卷 36, 期 8, 页码 -出版社
WILEY
DOI: 10.1096/fj.202200312R
关键词
photolabeling; propofol; TLR7 antagonist
资金
- CHMC Anesthesia Foundation
- NIH [R21AI158886]
Sedatives/anesthetics can modulate immune functions, but their effect on TLR7 function is not well understood. This study found that propofol attenuates TLR7 activation and reduces immune response triggered by TLR7 agonist.
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-alpha, IL-1 beta, IL-6, IL-10, and IFN-beta 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-beta expression in the lungs, and propofol attenuated IFN-beta 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.
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