TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes.

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.

Exogenous activation of tumor necrosis factor receptor 2 promotes recovery from sensory and motor disease in a model of multiple sclerosis.

Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that promotes immune modulation and tissue regeneration and is recognized as a potential therapeutic target for multiple sclerosis (MS). However, TNFR2 also contributes to T effector cell function and macrophage-TNFR2 recently was shown to promote disease development in the experimental autoimmune encephalomyelitis (EAE) model of MS. We here demonstrate that systemic administration of a TNFR2 agonist alleviates peripheral and central inflammation, and reduces demyelination and neurodegeneration, indicating that protective signals induced by TNFR2 exceed potential pathogenic TNFR2-dependent responses. Our behavioral data show that systemic treatment of female EAE mice with a TNFR2 agonist is therapeutic on motor symptoms and promotes long-term recovery from neuropathic pain. Mechanistically, our data indicate that TNFR2 agonist treatment follows a dual mode of action and promotes both suppression of CNS autoimmunity and remyelination. Strategies based on the concept of exogenous activation of TNFR2 therefore hold great promise as a new therapeutic approach to treat motor and sensory disease in MS as well as other inflammatory diseases or neuropathic pain conditions.