Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1–induced mechanisms

Zsuzsanna Helyes, Valéria Tékus, Nikolett Szentes, Krisztina Pohóczky, Bálint Botz, Tamás Kiss, Ágnes Kemény, Zsuzsanna Környei, Krisztina Tóth, Nikolett Lénárt, Hajnalka Ábrahám, Emmanuel Pinteaux, Sheila Francis, Serena Sensi, Ádám Dénes, Andreas Goebel

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Abstract

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-1αβ 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-1β floxed(fl/fl) mouse line, we demonstrated that CRPS IgG-induced changes are in part mediated by microglia-derived IL-1β, 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.

Original languageEnglish
Pages (from-to)13067-13076
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number26
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • Anakinra
  • Autoantibody
  • CRPS
  • Complex regional
  • Interleukin-1
  • Pain syndrome

ASJC Scopus subject areas

  • General

Cite this

Helyes, Z., Tékus, V., Szentes, N., Pohóczky, K., Botz, B., Kiss, T., Kemény, Á., Környei, Z., Tóth, K., Lénárt, N., Ábrahám, H., Pinteaux, E., Francis, S., Sensi, S., Dénes, Á., & Goebel, A. (2019). Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1–induced mechanisms. Proceedings of the National Academy of Sciences of the United States of America, 116(26), 13067-13076. https://doi.org/10.1073/pnas.1820168116