Monocyte NLRP3-IL-1β Hyperactivation Mediates Neuronal and Synaptic Dysfunction in Perioperative Neurocognitive Disorder.
Monocyte NLRP3-IL-1β Hyperactivation Mediates Neuronal and Synaptic Dysfunction in Perioperative Neurocognitive Disorder.
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DOI：
10.1002/advs.202104106
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发表时间：
2022-05
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围手术期神经认知障碍可能会在大手术后的弱势患者中发展。虽然神经炎症与手术的认知效应有关，但手术和免疫信号如何调节神经元回路，导致学习和记忆障碍仍然未知。使用体内双光子显微镜，对胸部手术小鼠模型的初级运动皮层中第5层锥体神经元的Ca 2+活性和突触后树突棘进行成像。研究发现，手术导致神经元活动减退，学习依赖性树突棘形成受损，以及多种学习任务的缺陷。皮质中的这些神经元和突触改变由外周单核细胞通过NLRP 3炎性体依赖性IL-1β产生介导。手术前消耗外周单核细胞或灭活NLRP 3炎性小体可降低IL-1β水平，并改善小鼠的神经元和行为缺陷。此外，过继转移来自进行胸部手术的小鼠的产生IL-1β的髓样细胞足以诱导幼稚小鼠的神经元和行为缺陷。总之，这些研究结果表明，手术导致单核细胞中NLRP 3过度活化和IL-1β信号传导升高，这反过来又导致神经元功能减退和围手术期神经认知障碍。围手术期神经认知障碍可能会在大手术后的弱势患者中发展。手术诱导的炎症反应如何调节神经元回路，从而影响认知功能仍不清楚。在小鼠中使用体内成像和细胞类型特异性操作，该研究揭示了外周单核细胞通过过度的NLRP 3激活和升高的IL-1β信号传导介导手术后的神经元和突触缺陷。
Perioperative neurocognitive disorder may develop in vulnerable patients following major operation. While neuroinflammation is linked to the cognitive effects of surgery, how surgery and immune signaling modulate neuronal circuits, leading to learning and memory impairment remains unknown. Using in vivo two‐photon microscopy, Ca2+ activity and postsynaptic dendritic spines of layer 5 pyramidal neurons in the primary motor cortex of a mouse model of thoracic surgery are imaged. It is found that surgery causes neuronal hypoactivity, impairments in learning‐dependent dendritic spine formation, and deficits in multiple learning tasks. These neuronal and synaptic alterations in the cortex are mediated by peripheral monocytes through the NLRP3 inflammasome‐dependent IL‐1β production. Depleting peripheral monocytes or inactivating NLRP3 inflammasomes before surgery reduces levels of IL‐1β and ameliorates neuronal and behavioral deficits in mice. Furthermore, adoptive transfer of IL‐1β‐producing myeloid cells from mice undertaking thoracic surgery is sufficient to induce neuronal and behavioral deficits in naïve mice. Together, these findings suggest that surgery leads to excessive NLRP3 activation in monocytes and elevated IL‐1β signaling, which in turn causes neuronal hypoactivity and perioperative neurocognitive disorder. Perioperative neurocognitive disorder may develop in vulnerable patients following major surgery. How surgery‐induced inflammatory responses modulate neuronal circuits and thereby affect cognitive functioning remains unclear. Using in vivo imaging and cell type‐specific manipulation in mice, this study reveals that peripheral monocytes mediate neuronal and synaptic deficits after surgery through excessive NLRP3 activation and elevated IL‐1β signaling.