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 10

HAAO-derived QA mediates neuropathic pain through the upmodulation of NMDA currents.

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HAAO-derived QA mediates neuropathic pain through the upmodulation of NM...
(A) Mechanical nociceptive threshold was evaluated before and up to 28 days after SNI and sham surgeries in 3-hydroxyanthranilic acid dioxygenase–knockout (Haao–/–) and Haao+/+ mice (n = 4–8). (B) Levels of quinolinic acid (QA) were determined in the contralateral and ipsilateral dorsal horn of the spinal cord of mice after SNI surgery (14 days after surgery; n = 9). (C) Representative images of in situ hybridization (RNAscope) analysis of Haao (magenta) triple stained for HAAO (green) and CD11c (red) immunoreactivity and DAPI (cell nuclei, blue) in the ipsilateral region containing DRG (L4), DRL, and spinal cord from mice harvested 14 days after SNI surgery. Scale bar: 128 μm. (D) Quantification of Haao and HAAO-expressing cells in the DRL from SNI mice (14 days after SNI) or sham mice (n = 3–5). (E) Mechanical nociceptive threshold was determined before and 14 days after SNI. Mice were treated intrathecally with vehicle or HAAO inhibitor (0.1 and 1 μmol) and mechanical allodynia was measured up to 24 hours after treatment (n = 6). Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 versus sham or vehicle; ###P < 0.001 versus Haao–/– mice by 2-way ANOVA with Bonferroni’s post hoc test (A and E) or unpaired 2-tailed Student’s t test (B and D).