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

JCI Insight. 2022 Mar 8;7(5):e154194. 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.

Keywords: Cellular immune response; Neuroscience; Pain; T cells.

MeSH terms

  • 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


  • Hepatitis A Virus Cellular Receptor 2
  • IL10 protein, mouse
  • Interleukin-13
  • Interleukin-10
  • Cisplatin