Annexin-A1 Tripeptide Attenuates Surgery-Induced Neuroinflammation and Memory Deficits Through Regulation the NLRP3 Inflammasome.
Annexin-A1 Tripeptide Attenuates Surgery-Induced Neuroinflammation and Memory Deficits Through Regulation the NLRP3 Inflammasome.
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DOI：
10.3389/fimmu.2022.856254
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发表时间：
2022
影响因子：
7.3
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中科院分区：
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神经炎症是围手术期神经认知障碍（PND）的一个日益增长的标志，包括谵妄和持续时间较长的认知缺陷。我们已经开发了一种临床相关的骨科小鼠模型，以研究普通外科手术对脆弱大脑的影响。PND的潜在机制仍不清楚。在此，我们评估了手术创伤对NLRP 3炎性体信号传导的影响，包括C57 BL 6/J雄性小鼠（成年（3个月）和老年（>18个月））海马中含有CARD（ASC）的骨化相关斑点样蛋白（ASC）、半胱天冬酶-1和IL-1β的表达。手术触发了CA 1海马小胶质细胞中ASC斑点的形成，但在NLRP 3和ASC敲除小鼠中没有诱导显著的形态学变化。由于目前没有治疗PND的方法，我们评估了来自内源性炎症终末分子Annexin-A1（ANXA 1）的仿生肽的神经保护作用。我们发现，这种肽（ANXA 1 sp）抑制术后NLRP 3炎性体激活，并防止海马中的小胶质细胞激活，减少PND样记忆缺陷。总之，我们的结果揭示了海马ANXA 1和NLRP 3炎性小体失调在触发术后神经炎症中的先前未被认识到的作用，为通过炎症的解决来推进PND的治疗提供了新的靶点。
Neuroinflammation is a growing hallmark of perioperative neurocognitive disorders (PNDs), including delirium and longer-lasting cognitive deficits. We have developed a clinically relevant orthopedic mouse model to study the impact of a common surgical procedure on the vulnerable brain. The mechanism underlying PNDs remains unknown. Here we evaluated the impact of surgical trauma on the NLRP3 inflammasome signaling, including the expression of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1β in the hippocampus of C57BL6/J male mice, adult (3-months) and aged (>18-months). Surgery triggered ASC specks formation in CA1 hippocampal microglia, but without inducing significant morphological changes in NLRP3 and ASC knockout mice. Since no therapies are currently available to treat PNDs, we assessed the neuroprotective effects of a biomimetic peptide derived from the endogenous inflammation-ending molecule, Annexin-A1 (ANXA1). We found that this peptide (ANXA1sp) inhibited postoperative NLRP3 inflammasome activation and prevented microglial activation in the hippocampus, reducing PND-like memory deficits. Together our results reveal a previously under-recognized role of hippocampal ANXA1 and NLRP3 inflammasome dysregulation in triggering postoperative neuroinflammation, offering a new target for advancing treatment of PNDs through the resolution of inflammation.