Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice
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
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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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 5

Cells expressing IDO1 accumulate in the DRL after SNI and contribute to the maintenance of neuropathic pain.

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Cells expressing IDO1 accumulate in the DRL after SNI and contribute to ...
(A) Time course of IDO1 expression in the DRGs plus DRL tissues (n = 4 per time point). (B) Representative images showing immunoreactivity for IDO1 (red color) double labeled with DAPI (cell nuclei, blue) in the ipsilateral region containing DRG (L4), DRL, and spinal cord (SC) from SNI mice (14 days after SNI). Scale bars: 100 μm. (C) Quantification of IDO1-expressing cells in the DRL from SNI mice (14 days after SNI) or sham mice (n = 6). (D) Time course of kynurenine levels in the ipsilateral dorsal horn of the spinal cord of mice after sham (14 days) and SNI surgeries (n = 5 per time point). (E) Mechanical nociceptive threshold was determined before and 14 days after SNI. Mice were treated intrathecally with vehicle or 1-methyl-DL-tryptophan (1-MT, 0.15–15 μg/site) and mechanical allodynia was measured up to 7 hours after treatment (n = 5). Data are expressed as mean ± SEM. *P < 0.05, **P < 0.001 versus sham group; #P < 0.05 versus vehicle-treated mice by 1-way ANOVA with Bonferroni’s post hoc test (A and D), unpaired 2-tailed Student’s t test (C), or 2-way ANOVA with Bonferroni’s post hoc test (E).