Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA.
J Neuroinflammation. 2018 Apr 11;15(1):105. doi: 10.1186/s12974-018-1145-1.
Both dysfunctional neuropeptide signaling and immune system activation are characteristic of complex regional pain syndrome (CRPS). Unknown is whether substance P (SP) or calcitonin gene-related peptide (CGRP) support autoantibody production and, consequently, nociceptive sensitization.
These experiments involved the use of a well-characterized tibia fracture model of CRPS. Mice deficient in SP expression (Tac1) and CGRP signaling (RAMP1) were used to probe the neuropeptide dependence of post-fracture sensitization and antibody production. The deposition of IgM in the spinal cord, sciatic nerves, and skin was followed using Western blotting, as was expression of the CRPS-related autoantigen cytokeratin 16 (Krt16). Passive serum transfer to B-cell-deficient muMT mice was used to assess the production of functional autoantibodies in CRPS model mice. The use of immunohistochemistry allowed us to assess neuropeptide-containing fiber distribution and Langerhans cell abundance in mouse and human CRPS patient skin, while Langerhans cell-deficient mice were used to assess the functional contributions of these cells.
Functional SP and CGRP signaling were required both for the full development of nociceptive sensitization after fracture and the deposition of IgM in skin and neural tissues. Furthermore, the passive transfer of serum from wildtype but not neuropeptide-deficient mice to fractured muMT mice caused enhanced allodynia and postural unweighting. Langerhans cells were increased in number in the skin of fracture mice and CRPS patients, and those increases in mice were reduced in neuropeptide signaling-deficient animals. Unexpectedly, Langerhans cell-deficient mice showed normal nociceptive sensitization after fracture. However, the increased expression of Krt16 after tibia fracture was not seen in neuropeptide-deficient mice.
Collectively, these data support the hypothesis that neuropeptide signaling in the fracture limb of mice is required for autoantigenic IgM production and nociceptive sensitization. The mechanism may be related to neuropeptide-supported autoantigen expression.
神经肽信号功能障碍和免疫系统激活是复杂性区域疼痛综合征（CRPS）的特征。目前尚不清楚 P 物质（SP）或降钙素基因相关肽（CGRP）是否支持自身抗体的产生，从而导致痛觉敏化。
本研究使用了一种经过充分验证的胫骨骨折 CRPS 模型。利用缺乏 SP 表达（Tac1）和 CGRP 信号（RAMP1）的小鼠来探究神经肽在后骨折敏化和抗体产生中的依赖性。通过 Western blot 检测脊髓、坐骨神经和皮肤中 IgM 的沉积情况，以及与 CRPS 相关的自身抗原细胞角蛋白 16（Krt16）的表达情况。将血清被动转移到 B 细胞缺陷型 muMT 小鼠中，以评估 CRPS 模型小鼠中功能性自身抗体的产生。免疫组织化学方法用于评估小鼠和人类 CRPS 患者皮肤中含神经肽纤维的分布和朗格汉斯细胞的丰度，同时使用朗格汉斯细胞缺陷型小鼠来评估这些细胞的功能贡献。
功能性 SP 和 CGRP 信号对于骨折后痛觉敏化的完全发展和 IgM 在皮肤和神经组织中的沉积都是必需的。此外，将来自野生型而非神经肽缺陷型小鼠的血清被动转移到骨折 muMT 小鼠中，会导致痛觉过敏和姿势减重加重。骨折小鼠和 CRPS 患者皮肤中的朗格汉斯细胞数量增加，而在神经肽信号缺陷型动物中，这些增加的数量减少。出乎意料的是，朗格汉斯细胞缺陷型小鼠在骨折后表现出正常的痛觉敏化。然而，在神经肽缺陷型小鼠中，胫骨骨折后 Krt16 的表达增加并不明显。
综上所述，这些数据支持这样的假设，即小鼠骨折肢体中的神经肽信号对于自身抗原性 IgM 产生和痛觉敏化是必需的。其机制可能与神经肽支持的自身抗原表达有关。
