Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1-induced mechanisms
Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1-induced mechanisms
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DOI：
10.1073/pnas.1820168116
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发表时间：
2019-06-25
影响因子：
11.1
通讯作者：
Goebel, Andreas
中科院分区：
文献类型：
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作者：
Helyes, Zsuzsanna;Tekus, Valeria;Goebel, Andreas
复杂区域疼痛综合征(CRPS)是一种创伤后疼痛障碍，神经免疫相互作用可能导致严重疼痛以及局部炎症和自主神经体征。在这里，我们研究了CRPS的翻译被动转移创伤小鼠模型的外周和中枢免疫机制。对C57BL/6雌性小鼠进行足底皮肤肌肉小切口，每天用来自长期CRPS患者或健康志愿者的纯化血清免疫球蛋白G(IgG)治疗，然后评估足肿胀、痛觉过敏、炎症和中枢神经胶质细胞的激活。与正常对照组相比，CRPS-Ig G显著增加和延长了断掌的肿胀和稳定的痛觉过敏。在所有组小鼠都出现了短暂的爪部炎症反应后，注射CRPS免疫球蛋白的小鼠在脊髓背角和疼痛相关脑区显示出持续的、深刻的小胶质细胞和星形胶质细胞激活，表明中枢敏化。使用IL-1αβ基因敲除(KO)小鼠的IL-1基因缺失和围手术期IL-1受体1型(IL-1R1)被药物Anakinra阻断，但不能用糖皮质激素强的松龙治疗，阻止了这些变化。阿纳金纳治疗也逆转了已建立的致敏表型，在切开后8天开始治疗。此外，随着IL-1β((FL/FL))小鼠系的产生，我们证明CRPS免疫球蛋白诱导的变化部分是由小胶质细胞来源的IL-1β介导的，这表明外周和中枢性炎症机制都有助于转移的疾病表型。这些结果表明，持续性CRPS通常是由自身抗体引起的，并强调了临床许可的拮抗剂，如Anakinra，通过阻断IL-1的作用来预防或治疗CRPS的潜在治疗用途。
Neuroimmune interactions may contribute to severe pain and regional inflammatory and autonomic signs in complex regional pain syndrome (CRPS), a posttraumatic pain disorder. Here, we investigated peripheral and central immune mechanisms in a translational passive transfer trauma mouse model of CRPS. Small plantar skin-muscle incision was performed in female C57BL/6 mice treated daily with purified serum immunoglobulin G (IgG) from patients with longstanding CRPS or healthy volunteers followed by assessment of paw edema, hyperalgesia, inflammation, and central glial activation. CRPS IgG significantly increased and prolonged swelling and induced stable hyperalgesia of the incised paw compared with IgG from healthy controls. After a short-lasting paw inflammatory response in all groups, CRPS IgG-injected mice displayed sustained, profound microglia and astrocyte activation in the dorsal horn of the spinal cord and pain-related brain regions, indicating central sensitization. Genetic deletion of interleukin-1 (IL-1) using IL-1 alpha beta knockout (KO) mice and perioperative IL-1 receptor type 1 (IL-1R1) blockade with the drug anakinra, but not treatment with the glucocorticoid prednisolone, prevented these changes. Anakinra treatment also reversed the established sensitization phenotype when initiated 8 days after incision. Furthermore, with the generation of an IL-1 beta floxed((fl/fl)) mouse line, we demonstrated that CRPS IgG-induced changes are in part mediated by microglia-derived IL-1 beta, suggesting that both peripheral and central inflammatory mechanisms contribute to the transferred disease phenotype. These results indicate that persistent CRPS is often contributed to by autoantibodies and highlight a potential therapeutic use for clinically licensed antagonists, such as anakinra, to prevent or treat CRPS via blocking IL-1 actions.