Neuroinflammatory mechanisms of central sensitization are mediated by TNF- and IL1-driven pathways in a passive transfer-trauma mouse model of Complex Regional Pain Syndrome (CRPS) 
Nikolett Szentes1, Krisztina Pohóczky1,2, Valéria Tékus1, Bálint Botz1, Ágnes Kemény1,3, Tamás Kiss1, Zsuzsanna Környei5, Krisztina Tóth5, Serena Sensi6, Jenny Hawkes6, Ádám Dénes5, Andreas Goebel6,7, Zsuzsanna Helyes1,4
[1] University of Pécs, Medical School, Department of Pharmacology and Pharmacotherapy & János Szentágothai Research Centre, Centre for Neuroscience
[2] University of Pécs, Faculty of Pharmacy, Department of Pharmacology
[3] University of Pécs, Medical School, Department of Medical Biology
[4] PharmInVivo Ltd., Pécs, Hungary
[5] Momentum Laboratory of Neuroimmunology, Institute of Experimental Medicine, Hungary
[6] Department of Translational Medicine, University of Liverpool
[7] The Walton Centre NHS Foundation Trust, Liverpool
Background
Complex Regional Pain Syndrome (CRPS) is a severe chronic pain condition accompanied by hypersensitivity, swelling and autonomic dysfunctions after a small injury. The ethiology is unknown, but immune response against sensory nerve-derived antigens and complex neuro-immune interactions are involved. The therapy is unsatisfactory, therefore, there is need to explore the pathophysiological mechanisms and identify drug targets.
Methods
Female C57Bl/6 mice were treated daily with purified serum-IgG from CRPS patients or healthy volunteers following plantar skin-muscle incision. We determined the mechanonociceptive threshold, edeme, myeloperoxidase activity, inflammatory cytokines, microglia and astrocyte markers in pain-related brain regions. Fractalkin receptor (CX3CR1) gene-deficient mice were used to investigate microglia activation mechanisms. The effects of the interleukin 1 (IL-1) receptor antagonist anakinra, the inhibitor of its signaling Janus kinase tofacitinib, or the soluble tumor necrosis factor (TNF) receptor etanercept were investigated by 7-13-day experiments.
Results
Significantly greater mechanical hyperalgesia and paw edema developed after incision in CRPS IgG-treated mice accompanied by a significant increase of astrocyte and microglia markers. Myeloperoxidase activity increased in the early phase but inflammatory cytokine concentrations did not change. CX3CR1 gene deficiency, as well as anakinra, tofacitinib and etanercept treatments significantly reduced CRPS IgG-induced hyperalgesia and increase neuroinflammation. Anakinra treatment decreased myeloperoxidase activity and glia activation.
Conclusions
Autoantibody-induced neuroinflammation and central sensitization plays a crucial role in persistent CRPS-related pain. Glia activation is a key factor of this process via CX3CR1, IL-1- and TNF-signalling, through the JAK pathway. Blocking these receptors or inhibiting the signal transduction may represent new therapeutic perspectives.
Support: National Brain Research Program (2017-1.2.1-NKP-2017-00002); GINOP-2.3.2-15-2016-00050 „PEPSYS”; EFOP-3.6.1-16-2016-00004, NTP-NFTÖ-18-B-0454

NEUROINFLAMMATORY MECHANISMS OF CENTRAL SENSITIZATION ARE MEDIATED BY TNF- AND IL1-DRIVEN PATHWAYS IN A PASSIVE TRANSFER-TRAUMA MOUSE MODEL OF COMPLEX REGIONAL PAIN SYNDROME (CRPS)