Early regeneration of axons following peripheral nerve injury is enhanced if p75NTRis eliminated from the surrounding pathway
Early regeneration of axons following peripheral nerve injury is enhanced if p75NTRis eliminated from the surrounding pathway
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DOI：
10.1111/ejn.14943
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发表时间：
2020-09-09
影响因子：
3.4
通讯作者：
English, Arthur
中科院分区：
文献类型：
--
作者：
McGregor, Claire;Sabatier, Manning;English, Arthur
常见的神经营养蛋白受体 p75(NTR) 被认为是周围神经损伤后轴突再生的抑制剂，但这种作用是否对再生轴突、迁移到损伤部位的免疫细胞或轴突周围通路中的细胞产生影响尚不清楚。用非荧光宿主的移植物修复在轴突中表达荧光蛋白的小鼠的切断神经，以研究当 p75(NTR) 分别从切断神经近端残端的轴突和免疫细胞、再生途径中的细胞或两者中消除时，轴突伸长。两周后，再生为不含 p75(NTR) 的移植物的野生型小鼠的轴突伸长程度是野生型小鼠移植物中轴突的两倍多。无论是用野生型小鼠还是p75(NTR)敲除小鼠的移植物修复神经，都没有观察到p75(NTR)敲除小鼠的轴突再生增强。为了评估 p75(NTR) 的抑制是否可用于改善再生，在神经修复时，将未经移植修复的野生型小鼠的神经暴露于 p75(NTR) 受体的特异性抑制剂 LM11A-31。这种 p75(NTR) 的局部阻断导致轴突的成功再生，其数量是未治疗对照的近三倍，并且通过再生运动轴突，神经支配的肌肉纤维数量是未治疗对照的两倍。再生轴突周围 p75(NTR) 的表达导致周围神经损伤后前 2 周内再生不良。 p75(NTR) 的抑制可能是治疗周围神经损伤的治疗靶点。
The common neurotrophin receptor, p75(NTR), has been proposed to be an inhibitor of axon regeneration after peripheral nerve injury, but whether this effect is on the regenerating axons, immune cells migrating into the injury site, or cells in the pathway surrounding the axons is not clear. Cut nerves in mice expressing fluorescent proteins in axons were repaired with grafts from non-fluorescent hosts to study axon elongation when p75(NTR)was eliminated separately from axons and immune cells in the proximal stump of cut nerves, from cells in the regeneration pathway, or both. Two weeks later, axons from wild type mice regenerating into grafts devoid of p75(NTR)had elongated more than twice as far as axons in grafts from wild type mice. No enhancement of regeneration of axons in p75(NTR)knockout mice was observed, whether nerves were repaired with grafts from wild type mice or from p75(NTR)knockout mice. To evaluate whether inhibition of p75(NTR)could be used to improve regeneration, nerves in wild type mice repaired without grafts were exposed to a specific inhibitor of the p75(NTR)receptor, LM11A-31, at the time of nerve repair. This local blockade of p75(NTR)resulted in successful regeneration of axons of nearly three times as many motoneurons and reinnervation of twice as many muscle fibers by regenerating motor axons as untreated controls. Expression of p75(NTR)surrounding regenerating axons contributes to poor regeneration during the first 2 weeks after peripheral nerve injury. Inhibition of p75(NTR)might be a therapeutic target for treatments of peripheral nerve injuries.