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 6

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

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IDO1-expressing DCs accumulate in the DRL after SNI and contribute to th...
(A) Representative dot plots and quantification of CD45+CD11b–CD11c+ cells (DCs) in DRGs plus DRLs harvested 14 days after sham or SNI surgery from WT mice (n = 5). (B) Representative images showing immunoreactivity for IDO1 (red color) double labeled with anti-CD11c (DCs) in the ipsilateral DRLs (L4) from SNI mice (14 days after SNI). Scale bars: 50 μm (left) and 100 μm (right). (C) Mechanical nociceptive threshold was determined before and 13 days after SNI. Mice were treated intrathecally with vehicle or diphtheria toxin (Dtx, 20 ng/site) and mechanical allodynia was measured up to 48 hours after treatment (n = 5). (D) Western blotting analysis of IDO1 expression in the DRGs plus DRL tissues harvested 15 days after SNI mice were treated with vehicle or Dtx (n = 4). Data are expressed as mean ± SEM. *P < 0.05, ***P < 0.001, ****P < 0.0001 versus sham group by unpaired 2-tailed Student’s t test (A and D) or 1-way ANOVA with Bonferroni’s post hoc test (C).