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IF 9.3 1区医学 Q1 CLINICAL NEUROLOGY

Acta Neuropathologica Pub Date : 2024-12-16 DOI:10.1007/s00401-024-02840-9

Beate Hartmannsberger, Adel Ben-Kraiem, Sofia Kramer, Carolina Guidolin, Ida Kazerani, Kathrin Doppler, Dominique Thomas, Robert Gurke, Marco Sisignano, Pranav P. Kalelkar, Andrés J. García, Paula V. Monje, Michael Sammeth, Asma Nusrat, Alexander Brack, Susanne M. Krug, Claudia Sommer, Heike L. Rittner

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引用次数: 0

摘要

神经损伤会导致神经病理性疼痛和多层次神经屏障破坏。神经屏障包括神经周围屏障、内皮屏障和髓鞘屏障。迄今为止，尚不清楚重新修复神经屏障是否能促进疼痛的缓解和恢复。为此，我们分析了大鼠坐骨神经慢性收缩性损伤中神经屏障的特性组合、疼痛行为电池和脂质组学中的特化促疼痛缓解介质（SPMs）前体及其受体，以确定通过重新封闭所选神经屏障来缓解疼痛的靶点。在三种神经屏障（神经膜、毛细血管和髓鞘）中，只有毛细血管紧致度能特异性对抗纤维蛋白原等大分子，并随着疼痛的缓解而恢复。纤维蛋白原免疫反应不仅在大鼠神经病理性疼痛时升高，而且在疼痛性多发性神经病患者（而非无疼痛性多发性神经病患者）的神经活组织切片中也升高，这表明封闭血管屏障可能是治疗疼痛的一种新方法。羟基二十碳四烯酸（15R-HETE）是阿司匹林触发的脂质毒素 A4 的前体，在疼痛缓解初期会出现特异性上调。重复局部应用含有 resolvin D1 的纳米颗粒或 Fpr2 激动剂可加速疼痛的缓解和纤维蛋白原的清除，而这与性别无关。清除巨噬细胞（Cd206）得到增强，纤维蛋白溶解途径（Plat）得到诱导，而炎症（Tnfα）和炎性体（Nlrp3）则不受这种处理的影响。阻断 TAM 受体（Tyro3、Axl 和 Mer）和连接止血与炎症的酪氨酸激酶受体可完全抑制所有效应。总之，纳米颗粒可用作转瞬即逝的脂质（如 SPMs）的转运体，从而扩大了可能的治疗药物阵列。因此，Fpr2-Cd206-TAM 受体轴可能是加强毛细血管屏障、清除内膜纤维蛋白原和促进慢性神经病理性疼痛患者疼痛缓解的合适靶点。

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TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury

Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify targets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers—perineurium, capillaries and myelin—only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was elevated in rats not only at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy, indicating that sealing of the vascular barrier might be a novel approach in pain treatment. Hydroxyeicosatetraenoic acid (15R-HETE), a precursor of aspirin-triggered lipoxin A4, was specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (Cd206) were boosted and fibrinolytic pathways (Plat) were induced, while inflammation (Tnfα) and inflammasomes (Nlrp3) were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2–Cd206–TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen and boosting pain resolution in patients with chronic neuropathic pain.

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来源期刊

Acta Neuropathologica 医学-病理学

CiteScore

23.70

自引率

3.90%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.