Interleukin-6 trans-signalling in hippocampal CA1 neurones mediates perioperative neurocognitive disorders in mice
Interleukin-6 trans-signalling in hippocampal CA1 neurones mediates perioperative neurocognitive disorders in mice
复制标题
海马 CA1 神经元中的白细胞介素 6 反式信号传导介导小鼠围术期神经认知障碍
DOI：
10.1016/j.bja.2022.08.019
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发表时间：
2022-12-01
影响因子：
9.8
通讯作者：
Maze, Mervyn
中科院分区：
文献类型：
--
作者：
Hu, Jun;Zhang, Yu;Maze, Mervyn
背景资料：白细胞介素-6（IL-6）是一种具有退行性和再生性的多效性细胞因子，在小鼠无菌性创伤后引起围手术期神经认知障碍中是必要且充分的。IL-6通过经典信号传导与膜结合的IL-6受体a（mIL-6 Ra）结合后或通过反式信号传导与可溶性IL-6受体（IL-6 R）结合后启动其作用;两种信号传导途径都需要转换器gp 130。我们调查的网站和类型的IL-6信号，涉及在胫骨骨折无菌创伤模型围手术期neurocognitive disorder.Methods：野生型或基因改变的成年小鼠，缺乏独特的分子，无论是经典或trans-IL-6信号进行胫骨骨折异氟烷麻醉。在单独的队列中，我们使用微量恐惧条件反射范式（术后72小时）评估术后记忆，并使用CA 1海马神经元中信号转导和转录激活因子3（pSTAT 3）的磷酸化评估受体后IL-6信号传导（术后24小时）。在用BE 0047抑制两种形式的IL-6信号传导或仅用sgp 130 Fc抑制反式信号传导后，在术后第15天评估骨折愈合。记忆衰退的外科表型在手术前用BE 0047或sgp 130 Fc预处理后，未发生（在微量恐惧条件下的冻结减少）和上调的IL-6信号传导（pSTAT 3），或在耗尽来自CA 1神经元的gp 130之后。当IL-6 Ra在任一海马CA 1区神经元中被耗尽时，仍然发生手术表型（冷冻时间，38.9% [11.5%] vs 58.4% [12.3%]; pSTATthorn CA 1神经元，31.7 [4.9] vs 7.0 [3.1]）或小胶质细胞（冷冻时间，40.1% [13.9%] vs 65.2% [12.6%]; pSTATthorn CA 1神经元，30.1 [5.5] vs 7.9 [3.2]）。在整体IL-6 Rae/e小鼠中，当i. c. v.给药时，hyper-IL-6（反式信号激动剂）产生手术表型（冷冻时间，42.4% [8.8%] vs 59.7% [10.4%]; pSTATthorn细胞，29.3 [4.3] vs 10.0 [4.4]）。sgp 130 Fc组的骨折愈合率（骨折骨痂中新胶原蛋白的百分比）显著高于BE 0047组（52.2% [8.3%] vs 39.7% [7.9%]）。结论：骨科创伤后，IL-6通过IL-6在小鼠CA 1区神经元中的信号转导作用产生围手术期神经认知障碍。应寻求反式信号传导途径的药物靶点，以减少围手术期神经认知障碍，同时允许经典IL-6信号传导的愈合特性。
Background: Interleukin-6 (IL-6), a pleiotropic cytokine with both degenerative and regenerative properties, is necessary and sufficient to provoke perioperative neurocognitive disorders after aseptic trauma in mice. IL-6 initiates its actions after binding to either membrane-bound IL-6 receptor a (mIL-6Ra) through classical signalling, or soluble IL-6 receptor (IL-6R) through trans-signalling; both signalling pathways require the transducer gp130. We investigated the site and type of IL-6 signalling that pertains in a tibial fracture aseptic trauma model of perioperative neurocognitive disorder.Methods: Wild-type or genetically altered adult mice that lacked molecules unique to either classical or trans-IL-6 signalling underwent tibial fracture under isoflurane anaesthesia. In separate cohorts, we assessed postoperative memory using a trace fear conditioning paradigm (72 h postoperatively), and post-receptor IL-6 signalling (24 h postoperatively) using phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in CA1 hippocampal neurones. Fracture healing was assessed at postoperative day 15 after inhibiting either both forms of IL-6 signalling with BE0047 or only trans-signalling with sgp130Fc.Results: The surgical phenotype of memory decline (decrease in freezing in trace fear conditioning) and upregulated IL-6 signalling (pSTAT3) did not occur after pretreatment before surgery with either BE0047 or sgp130Fc, or after depleting gp130 from CA1 neurones. The surgical phenotype still occurred when IL-6Ra was depleted in either CA1 hippocampal neurones (freezing time, 38.9% [11.5%] vs 58.4% [12.3%]; pSTATthorn CA1 neurones, 31.7 [4.9] vs 7.0 [3.1]) or microglia (freezing time, 40.1% [13.9%] vs 65.2% [12.6%]; pSTATthorn CA1 neurones, 30.1 [5.5] vs 7.9 [3.2]). In global IL-6Rae/e mice, hyper-IL-6, the trans-signalling agonist, produced the surgical phenotype when administered i.c.v. (freezing time, 42.4% [8.8%] vs 59.7% [10.4%]; pSTATthorn cells, 29.3 [4.3] vs 10.0 [4.4]). Bone-fracture healing (% of fracture callus comprised of new collagen) was significantly greater with sgp130Fc than with BE0047 (52.2% [8.3%] vs 39.7% [7.9%]).Conclusions: After orthopaedic trauma, IL-6 produces perioperative neurocognitive disorders through IL-6 trans-signalling in mouse CA1 neurones. Druggable targets of the trans-signalling pathway should be sought to reduce perioperative neurocognitive disorders while allowing the healing properties of classical IL-6 signalling.