Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice
Alexandre G. Maganin, … , Andrew Mellor, Thiago M. Cunha
Alexandre G. Maganin, … , Andrew Mellor, Thiago M. Cunha
Published October 13, 2022
Citation Information: J Clin Invest. 2022;132(23):e153805. https://doi.org/10.1172/JCI153805.
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Research Article Metabolism Neuroscience

Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice

Abstract

Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO1-expressing dendritic cells (DCs) accumulated in the dorsal root leptomeninges and led to an increase in kynurenine levels in the spinal cord. In the spinal cord, kynurenine was metabolized by kynurenine-3-monooxygenase–expressing astrocytes into the pronociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase–derived quinolinic acid formed in the final step of the canonical KYNPATH was also involved in neuropathic pain development through the activation of the glutamatergic N-methyl-D-aspartate receptor. In conclusion, these data revealed a role for DCs driving neuropathic pain development through elevation of the KYNPATH. This paradigm offers potential new targets for drug development against this type of chronic pain.

Authors

Alexandre G. Maganin, Guilherme R. Souza, Miriam D. Fonseca, Alexandre H. Lopes, Rafaela M. Guimarães, André Dagostin, Nerry T. Cecilio, Atlante S. Mendes, William A. Gonçalves, Conceição E.A. Silva, Francisco Isaac Fernandes Gomes, Lucas M. Mauriz Marques, Rangel L. Silva, Letícia M. Arruda, Denis A. Santana, Henrique Lemos, Lei Huang, Marcela Davoli-Ferreira, Danielle Santana-Coelho, Morena B. Sant’Anna, Ricardo Kusuda, Jhimmy Talbot, Gabriela Pacholczyk, Gabriela A. Buqui, Norberto P. Lopes, Jose C. Alves-Filho, Ricardo M. Leão, Jason C. O’Connor, Fernando Q. Cunha, Andrew Mellor, Thiago M. Cunha

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Figure 3

Upregulation of IDO1 in peripheral hematopoietic cell compartment mediates neuropathic pain.

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Upregulation of IDO1 in peripheral hematopoietic cell compartment mediat...
(A) Western blotting analysis of IDO1 expression in the dorsal horn of the spinal cord with or without transcardiac perfusion with PBS after sham or SNI surgery (n = 4). (B) Time course of kynurenine levels in the serum of mice after sham (14 days) and SNI surgeries (n = 11–17 per time point). Time course of Ido1 mRNA (C) (n = 5–7 per time point) and protein (D) (n = 7 per time point) expression in the draining lymph nodes after sham or SNI surgery. (E) Time course of Ido1 mRNA expression in spleen after sham (14 days) or SNI surgeries (n = 7–8 per time point). (F) Mechanical nociceptive threshold of WT→WT, Ido1–/–→Ido1–/–, Ido1–/–→WT, and WT→Ido1–/– chimeric mice before (baseline, BL) and up to 28 days after SNI (n = 7). Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 versus sham; ##P < 0.01, ###P < 0.001 versus Ido1–/– mice or perfused group by 1-way ANOVA with Bonferroni’s post hoc test (A–E) or 2-way ANOVA with Bonferroni’s post hoc test (F).