CD8(+) T cell–derived IL-13 increases macrophage IL-10 to resolve neuropathic pain

Understanding the endogenous mechanisms regulating resolution of pain may identify novel targets for treatment of chronic pain. Resolution of chemotherapy-induced peripheral neuropathy (CIPN) after treatment completion depends on CD8(+) T cells and on IL-10 produced by other cells. Using Rag2(–/–) mice lacking T and B cells and adoptive transfer of Il13(–/–) CD8(+) T cells, we showed that CD8(+) T cells producing IL-13 were required for resolution of CIPN. Intrathecal administration of anti–IL-13 delayed resolution of CIPN and reduced IL-10 production by dorsal root ganglion macrophages. Depleting local CD206(+) macrophages also delayed resolution of CIPN. In vitro, TIM3(+)CD8(+) T cells cultured with cisplatin, apoptotic cells, or phosphatidylserine liposomes produced IL-13, which induced IL-10 in macrophages. In vivo, resolution of CIPN was delayed by intrathecal administration of anti-TIM3. Resolution was also delayed in Rag2(–/–) mice reconstituted with Havcr2 (TIM3)(–/–) CD8(+) T cells. Our data indicated that cell damage induced by cisplatin activated TIM3 on CD8(+) T cells, leading to increased IL-13 production, which in turn induced macrophage IL-10 production and resolution of CIPN. Development of exogenous activators of the IL-13/IL-10 pain resolution pathway may provide a way to treat the underlying cause of chronic pain.