TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes
Significance
Tumor necrosis factor (TNF) is a cytokine that induces signaling via two receptors, TNFR1 and TNFR2. TNF signaling via TNFR1 contributes to development and maintenance of neuropathic pain. Here, we show that TNFR2 is essential for recovery from neuropathic pain across sexes. Treatment of male and female neuropathic mice with a TNFR2 agonist resulted in long-lasting recovery from neuropathic pain. We identified Tregs as the cellular mediator of the analgesic effect of TNFR2. Indeed, TNFR2 agonist administration alleviated peripheral and central inflammation and promoted neuroprotection in a Treg-dependent manner, indicating that TNFR2-dependent modulation of immunity is neuroprotective. We therefore argue that TNFR2 agonists might be a class of nonopioid drugs that can promote long-lasting pain recovery in males and females.
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.