TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes

Proceedings of the National Academy of Sciences of the United States of America
Roman FischerJohn R Bethea

Abstract

Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that is linked to immune modulation and tissue regeneration. Here, we show that TNFR2 essentially promotes long-term pain resolution independently of sex. Genetic deletion of TNFR2 resulted in impaired neuronal regeneration and chronic nonresolving pain after chronic constriction injury (CCI). Further, pharmacological activation of TNFR2 using the TNFR2 agonist EHD2-sc-mTNFR2 in mice with chronic neuropathic pain promoted long-lasting pain recovery. TNFR2 agonist treatment reduced neuronal injury, alleviated peripheral and central inflammation, and promoted repolarization of central nervous system (CNS)-infiltrating myeloid cells into an antiinflammatory/reparative phenotype. Depletion of regulatory T cells (Tregs) delayed spontaneous pain recovery and abolished the therapeutic effect of EHD2-sc-mTNFR2 This study therefore reveals a function of TNFR2 in neuropathic pain recovery and demonstrates that both TNFR2 signaling and Tregs are essential for pain recovery after CCI. Therefore, therapeutic strategies based on the concept of enhancing TNFR2 signaling could be developed into a nonopioid therapy for the treatment of chronic neuropathic pain.

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Citations

Feb 23, 2020·Journal of Leukocyte Biology·Kamar-Sulu N AtretkhanySergei A Nedospasov
May 27, 2020·Oxidative Medicine and Cellular Longevity·Valentina PegorettiRoman Fischer
Jun 13, 2020·Frontiers in Cell and Developmental Biology·Roman FischerKlaus Pfizenmaier
Aug 28, 2020·Frontiers in Psychology·Ana Carolina Pinheiro CamposRaquel Chacon Ruiz Martinez
Dec 10, 2020·Science Signaling·Heather TorreyDenise L Faustman
Jan 13, 2021·Trends in Molecular Medicine·Annemieke Kavelaars, Cobi J Heijnen
Mar 8, 2021·The Journal of Pain : Official Journal of the American Pain Society·Jiajie LuGang Chen
Mar 12, 2021·Frontiers in Immunology·John R Bethea, Roman Fischer
May 28, 2021·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Kufreobong E InyangGeoffroy Laumet
Jun 22, 2021·International Reviews of Immunology·Kevin M HarrisLinda R Watkins
Jul 14, 2021·Pain·Ann M GregusMatthew W Buczynski
Jul 7, 2021·Nature Reviews. Rheumatology·Benoit L Salomon
Sep 9, 2021·Journal of Leukocyte Biology·Shaokui ChenXin Chen

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Methods Mentioned

BETA
flow cytometry
PCR

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