Hope for mitigation of the symptoms of a serious pain syndrome

2019. július 2.

The Hungarian leaders of the work were Zsuzsanna Helyes, professor of the Department of Pharmacy at the University of Pécs and President of the János Szentágothai Research Center, as well as Ádám Dénes, head of the Laboratory of Neuroimmunology at IEM HAS, recipient of the prestigious Momentum program and ERC Consolidator Grant winner.

Summary of the work

Neuro-immune interactions may contribute to severe pain, and inflammatory and autonomic signs in Complex Regional Pain Syndrome (CRPS). However, the pathophysiological mechanisms remain unclear and therapies are unsatisfactory. Here we investigated peripheral and central immune mechanisms in a passive transfer-trauma translational mouse model for CRPS, where small plantar skin-muscle incision was performed in female C57Bl/6 mice treated daily with purified serum-IgG from patients with longstanding CRPS, or healthy volunteers. CRPS IgG significantly increased and prolonged swelling, and induced stable hyperalgesia of the incised paw compared to healthy IgG. Following a short-lasting paw inflammatory response in all groups, CRPS mice displayed sustained 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 KO mice and perioperative IL-1 receptor 1 (IL-1R1) blockade with the drug anakinra, but not steroid treatment precluded the development of transferred CRPS. Anakinra also abrogated the established sensitization phenotype when initiated 8 days after incision. Furthermore, with the generation of a novel IL-1βfl/fl mouse line we demonstrated that these actions are in part mediated by microglia-derived IL-1β, suggesting that both peripheral and central inflammatory mechanisms contribute to the transferred CRPS phenotype. These results indicate that persistent CRPS is mediated by autoantibodies and highlight a novel therapeutic use for clinically licensed antagonists, such as anakinra, to prevent or treat CRPS via blocking IL-1 actions.

Zsuzsanna Helyes, Valéria Tékus, Nikolett Szentes, Krisztina Pohóczky, Bálint Botz, Tamás Kissa, Ágnes Kemény, Zsuzsanna Környei, Krisztina Tóth, Nikolett Lénárt, Hajnalka Ábrahám, Emmanuel Pinteaux, Sheila Francis, Serena Sensi, Ádám Dénes, and Andreas Goebel, Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin1–induced mechanisms.