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, and Andreas Goebel
PNAS June 25, 2019 116 (26) 13067-13076; first published June 10, 2019 https://doi.org/10.1073/pnas.1820168116

  1. Edited by David Julius, University of California, San Francisco, CA, and approved May 13, 2019 (received for review December 1, 2018)

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Significance

Complex regional pain syndrome (CRPS) is a poorly understood painful condition, which typically arises after distal limb trauma; 20% of patients may develop lifelong severe incessant pain with few therapeutic options. In this study, we show that immunoglobulin G autoantibodies from patients with severe, persistent CRPS, on transfer to hind paw-injured mice, elicit important features of the clinical condition and profound glial activation in pain-related brain regions. Blockade of the proinflammatory cytokine interleukin-1 (IL-1) both prevents and reverses these changes. Our findings suggest that antibody-mediated autoimmunity contributes to the development of severe CRPS after injury and that blockade of IL-1 actions may be an attractive therapeutic prospect. Investigation of autoantibody contribution to other unexplained chronic pain syndromes seems warranted.

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.

Footnotes

  • ↵1Z.H., V.T., and N.S. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: zsuzsanna.helyes{at}aok.pte.hu, denes.adam{at}koki.mta.hu, or andreasgoebel{at}rocketmail.com.

  • ↵3Á.D. and A.G. contributed equally to this work.

  • Author contributions: Z.H., V.T., E.P., Á.D., and A.G. designed research; Z.H., V.T., N.S., K.P., B.B., T.K., Á.K., Z.K., K.T., N.L., H.Á., S.F., S.S., Á.D., and A.G. performed research; Z.K., K.T., N.L., E.P., S.F., and Á.D. contributed new reagents/analytic tools; Z.H., V.T., N.S., K.P., B.B., H.Á., E.P., Á.D., and A.G. analyzed data; and Z.H., N.S., K.P., E.P., S.F., Á.D., and A.G. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820168116/-/DCSupplemental.

Published under the PNAS license.

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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
Proceedings of the National Academy of Sciences Jun 2019, 116 (26) 13067-13076; DOI: 10.1073/pnas.1820168116
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