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 6

In vivo, TIM3+CD8+ T cells promote resolution of CIPN.

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In vivo, TIM3+CD8+ T cells promote resolution of CIPN. (A) Male and fema...
(A) Male and female mice were treated with cisplatin (2 mg/kg i.p. on days 0, 1, and 2); on days 7 and 8 after the first dose of cisplatin, they were intrathecally injected with anti-TIM3 antibody or control IgG (10 μg/mouse/d) and mechanical allodynia was followed over time. Two-way repeated-measures ANOVA followed by Bonferroni’s multiple-comparison test for Cis+IgG versus Cis+anti-TIM3. *P < 0.05, **P < 0.01, ***P < 0.001; n = 4 male, 4 female/group. (B) AUC of the resolution phase (days 8–21) of the cisplatin-treated mice in A. Welch’s t test; ****P < 0.000.1 (C) Percentage of M1 (CD206–CD11c+) and (D) M2 (CD206+CD11c–) macrophages in the DRG of mice treated with cisplatin followed by anti-TIM3 or IgG as in A. One-way ANOVA followed by Dunnett’s multiple-comparison test; ****P < 0.0001, *P < 0.05; n = 4 male, 4 female/group. (E) Time course of change in mechanical sensitivity in male and female Rag2–/– mice reconstituted with either Havcr2 (TIM3)–/– CD8+ T cells or WT CD8+ T cells. Ten days after reconstitution, mice were treated with cisplatin (2 mg/kg i.p. on days 0, 1, and 2), and mechanical allodynia was monitored over time. Two-way repeated-measures ANOVA followed by Bonferroni’s multiple-comparison test. *P < 0.05, **P < 0.01; Rag2–/–+WT CD8+Cis n = 8 male, 5 female; Rag2–/–+Havcr2 (TIM3)–/– CD8+Cis n = 8 male, 7 female. (F) AUC of the resolution phase (days 7–21) of the data in C; Welch’s t test; ***P < 0.01. (G) Percentage of IL-13+CD8+ T cells in DRG of Rag2–/– mice reconstituted with either Havcr2 (TIM3)–/– CD8+ T cells or WT CD8+ T cells treated with cisplatin. Welch’s t test; **P < 0.01. n = 4–7 male, 5 female/group. All data are shown as mean ± SEM.