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Orthopedic surgery-induced cognitive dysfunction is mediated by CX3CL1/R1 signaling

  • Cho, Inja1, 2
  • Kim, Jeong Min1, 2
  • Kim, Eun Jung1, 2
  • Kim, So Yeon1, 2
  • Kam, Eun Hee1, 2
  • Cheong, Eunji3
  • Suh, Minah4, 5, 6, 6
  • Koo, Bon-Nyeo1, 2
  • 1 Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea , Seoul (South Korea)
  • 2 Yonsei University College of Medicine, Seoul, Korea , Seoul (South Korea)
  • 3 Yonsei University, Seoul, Republic of Korea , Seoul (South Korea)
  • 4 Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon-si, Gyeong gi-do, 16419, Republic of Korea , Suwon-si (South Korea)
  • 5 Sungkyunkwan University, Suwon, Korea , Suwon (South Korea)
  • 6 Sungkyunkwan University, Suwon, 16419, South Korea , Suwon (South Korea)
Published Article
Journal of Neuroinflammation
Springer (Biomed Central Ltd.)
Publication Date
Apr 15, 2021
DOI: 10.1186/s12974-021-02150-x
Springer Nature


BackgroundPostoperative pain is a common phenomenon after surgery and is closely associated with the development of postoperative cognitive dysfunction (POCD). Persistent pain and systemic inflammation caused by surgery have been suggested as key factors for the development of POCD. Fractalkine (CX3CL1) and its receptor, the CX3C chemokine receptor 1 (CX3CR1), are known to play a key role in pain and inflammation signaling pathways. Recent studies have shown that the regulation of CX3CR1/L1 signaling influences the development of various diseases including neuronal diseases. We determined whether CX3CR1/L1 signaling is a putative therapeutic target for POCD in a mouse model.MethodsAdult (9–11 weeks) male mice were treated with neutralizing antibody to block CX3CR1/L1 signaling both before and after surgery. Inflammatory and behavioral responses including pain were assessed postoperatively. Also, CX3CR1 mRNA level was assessed. Hippocampal astrocyte activation, Mao B expression, and GABA expression were assessed at 2 days after surgery following neutralizing antibody administration.ResultsThe behavioral response indicated cognitive dysfunction and development of pain in the surgery group compared with the control group. Also, increased levels of pro-inflammatory cytokines and CX3CR1 mRNA were observed in the surgery group. In addition, increased levels of GABA and increased Mao B expression were observed in reactive astrocytes in the surgery group; these responses were attenuated by neutralizing antibody administration.ConclusionsIncreased CX3CR1 after surgery is both necessary and sufficient to induce cognitive dysfunction. CX3CR1 could be an important target for therapeutic strategies to prevent the development of POCD.

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