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 4

DC-expressed IDO1 contributes to the maintenance of neuropathic pain.

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DC-expressed IDO1 contributes to the maintenance of neuropathic pain. (A...
(A) Ido1 mRNA expression in CD11c+ or CD11c– cells isolated from the draining lymph nodes 14 days after sham or SNI surgery (n = 2 pooled from 5). (B) Representative scheme of chimeric CD11cDTR/hema mice establishment. (C) Mechanical nociceptive threshold was determined before and up to 12 days after sham or SNI surgery in chimeric CD11cDTR/hema mice treated with vehicle or diphtheria toxin (Dtx; 16 ng Dtx/g, i.p.) (n = 6). (D) Representative dot plots and quantification (percentage) of CD11c+ DCs in the draining lymph nodes harvested 14 days after sham or SNI surgery from chimeric CD11cDTR/hema mice treated with vehicle or Dtx (n = 6–10). (E) Western blotting analysis of IDO1 expression in the draining lymph nodes harvested 14 days after sham or SNI surgery from chimeric CD11cDTR/hema mice treated with vehicle or Dtx (n = 3). (F) Representative scheme of DC differentiation and transfer to Ido1–/– or WT mice. (G) Mechanical nociceptive threshold before (BL) and up to 14 days after sham or SNI in WT and Ido1–/– mice that received in vitro–differentiated DCs 1 day after surgeries (n = 5–6). (H) Mechanical nociceptive threshold was evaluated before and up to 21 days after SNI surgery in mice conditionally lacking Ido1 in CD11c+ cells (CD11c-Cre+/– Ido1fl/fl mice) or control littermates (CD11c-Cre–/– Ido1fl/fl) (n = 4–6). Data are expressed as mean ± SEM. **P < 0.01, ***P < 0.001, ****P < 0.0001 versus sham littermate control; ###P < 0.001 versus WT mice or treatment; §§§P < 0.001 versus BM Ido1–/– by 1-way ANOVA with Bonferroni’s post hoc test (A, D, and E) or 2-way ANOVA with Bonferroni’s post hoc test (C, G, and H).