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 1

IL-13 production by CD8+ T cells is required for resolution of cisplatin-induced mechanical allodynia.

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IL-13 production by CD8+ T cells is required for resolution of cisplatin...
(A) Male and (B) female mice were treated with cisplatin (3 daily doses of 2 mg/kg i.p.); on days 7 and 8, mice were intrathecally injected with anti–IL-13 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 at individual time points: Cis+IgG versus Cis+anti–IL-13; *P < 0.05, **P < 0.01, ***P < 0.001. Males: PBS+anti–IL-13: n = 4; females: Cis+IgG and Cis+anti–IL-13: n = 9. (C) Resolution of mechanical allodynia expressed as AUC between days 7 and 21. Two-way ANOVA: ***P < 0.001 main effect anti–IL-13; interaction: not significant; Bonferroni’s multiple-comparison: no differences between males and females. (D) IL-13+CD8+ T cells and (E) IL-13+CD4+ T cells in the DRG during CIPN resolution quantified by flow cytometry. Welch’s t test; *P < 0.05; n = 5 males + 2–3 females/group for D and n = 5 males/group for E. (F) Experimental setup for examining the role of IL-13–producing CD8+ T cells in resolution of CIPN. (G) Time course of change in mechanical sensitivity in male and female Rag2–/– mice reconstituted with WT or Il13–/– CD8+ T cells or not receiving any cells. Two-way repeated-measures ANOVA followed by Bonferroni’s multiple-comparison test at each time point for Rag2–/– reconstituted with WT versus Il13–/– CD8+ T cells: *P < 0.05; Rag2–/–+WT CD8+PBS, n = 3 male, 2 female; Rag2–/–+WT CD8+Cis, n = 5 male, 4 female; Rag2–/–+Il13–/– CD8+Cis, n = 5 male, 4 female; Rag2–/–+No CD8+Cis, n = 3 male, 2 female. (H) Resolution of mechanical allodynia expressed as AUC between days 11 and 21. One-way ANOVA followed by Tukey’s multiple-comparison test: *P < 0.05; ****P < 0.0001. All data represent mean ± SEM.