CD8+ T cell–derived IL-13 increases macrophage IL-10 to resolve neuropathic pain
Susmita K. Singh, Karen Krukowski, Geoffroy O. Laumet, Drew Weis, Jenolyn F. Alexander, Cobi J. Heijnen, Annemieke Kavelaars
Susmita K. Singh, Karen Krukowski, Geoffroy O. Laumet, Drew Weis, Jenolyn F. Alexander, Cobi J. Heijnen, Annemieke Kavelaars
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Research Article Neuroscience

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

Abstract

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.

Authors

Susmita K. Singh, Karen Krukowski, Geoffroy O. Laumet, Drew Weis, Jenolyn F. Alexander, Cobi J. Heijnen, Annemieke Kavelaars

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Figure 2

IL-13 mediates the cisplatin-induced increase in IL-10 production by macrophages.

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IL-13 mediates the cisplatin-induced increase in IL-10 production by mac...
(A) Schematic representation of cocultures of bone marrow–derived macrophages (BMDMs) and CD8+ T cells isolated from spleen treated in vitro with cisplatin (1, 2.5, and 5 μg/mL) or left untreated (unstim.); 24 hours later, the cells were assayed for (B) IL-10–containing F4/80+ macrophages and (C) CD8+ T cells by flow cytometry. One-way ANOVA followed by Dunnett’s multiple-comparison test, *P < 0.05, **P < 0.01; n = 3 independent experiments; 2 male, 1 female. (D) Schematic representation of cocultures of BMDMs and CD8+ T cells treated with cisplatin (1 μg/mL) in the presence of neutralizing anti–IL-13 antibody or control IgG or left untreated (unstim.). (E) Cells were assayed for IL-10+F4/80+macrophages by flow cytometry 48 hours later. One-way ANOVA followed by Tukey’s multiple-comparison test. ****P < 0.0001; n = 6 independent experiments; 3 male, 3 female. (F) Isolated CD8+ T cells were cultured with or without cisplatin (1 μg/mL) and assayed for IL-13 by flow cytometry. Welch’s t test; **P < 0.01; n = 5 independent experiments; 2 male, 3 female. All data are shown as mean ± SEM.