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Let-7b-TLR7 Signaling Axis Contributes to the Anesthesia/Surgery-Induced Cognitive Impairment

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Abstract

Perioperative neurocognitive disorders (PNDs) are severe and common neurological complications among elderly patients following anesthesia and surgery. As the first line of defense of the innate immune system, Toll-like receptors (TLRs) have been found to be involved in the occurrence of neurodegenerative diseases in recent years. However, the role of TLR7 in the pathology and development of PNDs remains largely unclear. In our current study, we hypothesized that increased microRNA let-7b (let-7b) during anesthesia and surgical operation would activate TLR7 signaling pathways and mediate PNDs. Using a mouse model of PNDs, 18–20 months wild-type (WT) mice were undergoing unilateral nephrectomy, and increased TLR7 and let-7b expression levels were found in the surgery group compared with the Sham group. Of note, increased TLR7 was found to be co-localized with let-7b in the hippocampal area CA1 in the PNDs model. In addition, TLR7 and let-7b inhibition could improve hippocampus-dependent memory and attenuate the production of inflammatory cytokines. Together, our results indicated that TLR7 activation and up-regulation might be triggered by increased let-7b under stressful conditions and initiated the downstream inflammatory signaling, playing a substantial role in the development of PNDs.

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Data Availability

The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank and express their heartfelt gratitude to Hongying Chen, Yan Wang, Huifang Li, Xiangyi Ren, Mengli Zhu, Li Fu, and Cong Li. (Cytology and Molecular Platform, Core Facilities of West China Hospital) for their assistance and guidance.

Funding

This work was supported by the National Natural Science Foundation of China (No.82171185, No. 81870858 to Dr. Chan Chen); The National Key R&D Program of China (No. 2018YFC2001800, to Dr. Tao Zhu) and the National Natural Science Foundation of China (No. 81671062, to Dr. Tao Zhu); The National Natural Science Foundation of China (No. 82201426 to Rui Gao); The Natural Science Foundation of Sichuan Province (No. 2022NSFSC1322 to Rui Gao); The China Postdoctoral Science Foundation (No. 2020 M673234 to Rui Gao); The Postdoctoral Research Project, West China Hospital, Sichuan University (No. 2020HXBH022 to Rui Gao).

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  1. Liyun Deng and Rui Gao contributed equally to this work and share the first authorship.

Authors and Affiliations

  1. Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China

    Liyun Deng, Rui Gao, Bo Jiao, Changteng Zhang, Liuxing Wei, Caiyi Yan, Tao Zhu & Chan Chen

  2. The Research Units of West China (2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu, China

    Liyun Deng, Rui Gao, Bo Jiao, Changteng Zhang, Liuxing Wei, Caiyi Yan, Tao Zhu & Chan Chen

  3. Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, China

    Hai Chen

  4. Unité INSERM U1195, Diseases and Hormones of the Nervous System, University of Paris-Scalay, Bicêtre Hosptial, Bât. Grégory Pincus, Le Kremlin-Bicêtre, France

    Shixin Ye-Lehmann

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Contributions

Conceptualization: Liyun Deng, Rui Gao, and Chan Chen; Methodology: Bo Jiao and Changteng Zhang; Formal analysis and investigation: Liyun Deng, Liuxing Wei, and Caiyi Yan; Writing—original draft preparation: Liyun Deng, Rui Gao; Writing—review and editing: Chan Chen and Tao Zhu; Funding acquisition: Rui Gao, Tao Zhu, and Chan Chen; Resources: Hai Chen, Shixin Ye-Lehmann; Supervision: Tao Zhu, Chan Chen. All authors reviewed the manuscript.

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Correspondence to Chan Chen.

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Supplement Figure 1

Changes in cognitive function at different days after unilateral nephrectomy. a Percentage of freezing time in the fear conditioning test of aged mice on the 1st, 3rd, and 7th day after unilateral nephrectomy. b Percentage of novel arm time in the Y maze test of aged mice on the 1st, 3rd, and 7th day after unilateral nephrectomy. c Mean velocity in open field test of aged mice on the 1st, 3rd, and 7th day after unilateral nephrectomy. d The number of rearing in open field test of aged mice on the 1st, 3rd, and 7th day after unilateral nephrectomy. e Total travel distance in open field test of aged mice on the 1st, 3rd, and 7th day after unilateral nephrectomy. Data are presented as mean ± SEM (n = 6 per group).(PNG 81 kb)

High Resolution (TIF 5707 kb)

Supplement Figure 2

The stereotactic injection and decreased expression of TLR7 did not influence the cognitive function of aged mice in the physiological state. a Schematic outline of the experimental protocol. b. The representative image of the needle track and distribution of the mouse receiving injection of 2μl Evans blue in the CA1 of each hemisphere. On the right side, the injection channel can be identified. c Percentage of freezing time and representative chart fear conditioning test experiment. d Percentage of novel arm time in Y-maze. e Mean velocity, number of rearing, and total travel distance in open field test of aged mice following unilateral nephrectomy. Data are presented as mean ± SEM (n = 6 per group).(PNG 289 kb)

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Deng, L., Gao, R., Chen, H. et al. Let-7b-TLR7 Signaling Axis Contributes to the Anesthesia/Surgery-Induced Cognitive Impairment. Mol Neurobiol 61, 1818–1832 (2024). https://doi.org/10.1007/s12035-023-03658-4

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