Extracellular RNAs-TLR3 signaling contributes to cognitive decline in a mouse model of postoperative cognitive dysfunction

Chan Chen, Rui Gao, Ming Li, Qiao Wang, Hai Chen, Shu Zhang, Xiaobo Mao, Adam Behensky, Zheng Zhang, Lu Gan, Tao Li, Ren Liao, Qian Li, Hai Yu, Jing Yang, Tao Zhu, Jin Liu

Research output: Contribution to journalArticle

Abstract

Postoperative cognitive dysfunction (POCD) is considered a severe complication after surgery among elderly patients. Toll-like receptor 3 (TLR3) has recently been reported to play an important role in hippocampus-dependent working memory. However, the role of TLR3 in the development of POCD remains unclear. In the current study, we hypothesized that increased extracellular RNAs (exRNAs) during anesthesia and surgical operation, especially double stranded RNAs (dsRNAs), would activate TLR3 signaling pathways and mediate POCD. Using a mouse model of POCD, 20–22 months wild-type (WT) mice were undergoing unilateral nephrectomy and increased TLR3 expression levels and co-localization with neuronal and microglial cells were found in the surgery group compared with the sham group. Compared with WT mice, TLR3 knockout (KO, −/− ) mice had improved hippocampus-dependent memory and attenuated production of inflammatory cytokines and apoptosis. Increased exRNAs and/or co-localization with TLR3 were found in both in vitro and in vivo models. Of note, TLR3/dsRNA complex inhibitor administration reduced hippocampal dsRNA level and TLR3 expression, attenuated hippocampal inflammatory cytokines production and apoptosis, and thus improved hippocampus-dependent memory. Our results indicate that exRNAs, especially dsRNAs, present under stressful conditions may trigger TLR3 activation and initiate the downstream inflammatory and apoptotic signaling, and play a substantial role in the development of POCD.

Original languageEnglish (US)
JournalBrain, Behavior, and Immunity
DOIs
StatePublished - Jan 1 2019

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Toll-Like Receptor 3
RNA
Hippocampus
Double-Stranded RNA
Cytokines
Cognitive Dysfunction
Nephrectomy
Short-Term Memory
Knockout Mice
Anesthesia
Apoptosis

Keywords

  • Aged mice
  • Apoptosis
  • Double stranded RNAs
  • Extracellular RNAs
  • Inflammatory response
  • Postoperative cognitive dysfunction
  • Toll-like receptor 3

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

Cite this

Extracellular RNAs-TLR3 signaling contributes to cognitive decline in a mouse model of postoperative cognitive dysfunction. / Chen, Chan; Gao, Rui; Li, Ming; Wang, Qiao; Chen, Hai; Zhang, Shu; Mao, Xiaobo; Behensky, Adam; Zhang, Zheng; Gan, Lu; Li, Tao; Liao, Ren; Li, Qian; Yu, Hai; Yang, Jing; Zhu, Tao; Liu, Jin.

In: Brain, Behavior, and Immunity, 01.01.2019.

Research output: Contribution to journalArticle

Chen, C, Gao, R, Li, M, Wang, Q, Chen, H, Zhang, S, Mao, X, Behensky, A, Zhang, Z, Gan, L, Li, T, Liao, R, Li, Q, Yu, H, Yang, J, Zhu, T & Liu, J 2019, 'Extracellular RNAs-TLR3 signaling contributes to cognitive decline in a mouse model of postoperative cognitive dysfunction', Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2019.04.024
Chen, Chan ; Gao, Rui ; Li, Ming ; Wang, Qiao ; Chen, Hai ; Zhang, Shu ; Mao, Xiaobo ; Behensky, Adam ; Zhang, Zheng ; Gan, Lu ; Li, Tao ; Liao, Ren ; Li, Qian ; Yu, Hai ; Yang, Jing ; Zhu, Tao ; Liu, Jin. / Extracellular RNAs-TLR3 signaling contributes to cognitive decline in a mouse model of postoperative cognitive dysfunction. In: Brain, Behavior, and Immunity. 2019.
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abstract = "Postoperative cognitive dysfunction (POCD) is considered a severe complication after surgery among elderly patients. Toll-like receptor 3 (TLR3) has recently been reported to play an important role in hippocampus-dependent working memory. However, the role of TLR3 in the development of POCD remains unclear. In the current study, we hypothesized that increased extracellular RNAs (exRNAs) during anesthesia and surgical operation, especially double stranded RNAs (dsRNAs), would activate TLR3 signaling pathways and mediate POCD. Using a mouse model of POCD, 20–22 months wild-type (WT) mice were undergoing unilateral nephrectomy and increased TLR3 expression levels and co-localization with neuronal and microglial cells were found in the surgery group compared with the sham group. Compared with WT mice, TLR3 knockout (KO, −/− ) mice had improved hippocampus-dependent memory and attenuated production of inflammatory cytokines and apoptosis. Increased exRNAs and/or co-localization with TLR3 were found in both in vitro and in vivo models. Of note, TLR3/dsRNA complex inhibitor administration reduced hippocampal dsRNA level and TLR3 expression, attenuated hippocampal inflammatory cytokines production and apoptosis, and thus improved hippocampus-dependent memory. Our results indicate that exRNAs, especially dsRNAs, present under stressful conditions may trigger TLR3 activation and initiate the downstream inflammatory and apoptotic signaling, and play a substantial role in the development of POCD.",
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AU - Mao, Xiaobo

AU - Behensky, Adam

AU - Zhang, Zheng

AU - Gan, Lu

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AB - Postoperative cognitive dysfunction (POCD) is considered a severe complication after surgery among elderly patients. Toll-like receptor 3 (TLR3) has recently been reported to play an important role in hippocampus-dependent working memory. However, the role of TLR3 in the development of POCD remains unclear. In the current study, we hypothesized that increased extracellular RNAs (exRNAs) during anesthesia and surgical operation, especially double stranded RNAs (dsRNAs), would activate TLR3 signaling pathways and mediate POCD. Using a mouse model of POCD, 20–22 months wild-type (WT) mice were undergoing unilateral nephrectomy and increased TLR3 expression levels and co-localization with neuronal and microglial cells were found in the surgery group compared with the sham group. Compared with WT mice, TLR3 knockout (KO, −/− ) mice had improved hippocampus-dependent memory and attenuated production of inflammatory cytokines and apoptosis. Increased exRNAs and/or co-localization with TLR3 were found in both in vitro and in vivo models. Of note, TLR3/dsRNA complex inhibitor administration reduced hippocampal dsRNA level and TLR3 expression, attenuated hippocampal inflammatory cytokines production and apoptosis, and thus improved hippocampus-dependent memory. Our results indicate that exRNAs, especially dsRNAs, present under stressful conditions may trigger TLR3 activation and initiate the downstream inflammatory and apoptotic signaling, and play a substantial role in the development of POCD.

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