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

• Published in: JCI insight Vol. 7; no. 5
• Main Authors: Singh, Susmita K, Krukowski, Karen, Laumet, Geoffroy O, Weis, Drew, Alexander, Jenolyn F, Heijnen, Cobi J, Kavelaars, Annemieke
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 08.03.2022; American Society for Clinical investigation
• Subjects: Animals; CD8-Positive T-Lymphocytes - metabolism; Chronic Pain; Cisplatin; Hepatitis A Virus Cellular Receptor 2 - metabolism; Hyperalgesia - chemically induced; Interleukin-10 - metabolism; Interleukin-13 - metabolism; Macrophages - metabolism; Mice; Neuralgia - complications; Neuroscience; Neuroscience; Pain; T cells; Cellular immune response
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.154194

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.