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Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):13067-13076. doi: 10.1073/pnas.1820168116. Epub 2019 Jun 10.

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

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Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary.
János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, H-7624, Pécs, Hungary.
PharmInVivo Ltd., H-7629, Pécs, Hungary.
Faculty of Pharmacy, Department of Pharmacology, University of Pécs, H-7624, Pécs, Hungary.
Department of Biology and Electron Microscopy, Medical School, University of Pécs, H-7624, Pécs, Hungary.
Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, H-1083, Budapest, Hungary.
Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester M13 9PT, United Kingdom.
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2RX, United Kingdom.
Department of Translational Medicine, University of Liverpool, Liverpool L9 7AL, United Kingdom.
Department of Pain Medicine, The Walton Centre National Health Service Foundation Trust, Liverpool L9 7LJ, United Kingdom.


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.


CRPS; anakinra; autoantibody; complex regional pain syndrome; interleukin-1

[Available on 2019-12-10]

Conflict of interest statement

The authors declare no conflict of interest.

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