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 7

KMO is upregulated in the spinal cord after SNI and mediates neuropathic pain.

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KMO is upregulated in the spinal cord after SNI and mediates neuropathic...
(A) Mechanical nociceptive threshold was evaluated before and up to 24 hours after intrathecal injection of equimolar doses (8 nmol) of kynurenine (Kyn), 3-hydroxykynurenine (3-Hk), 3-hydroxyanthranilic acid (3-Haa), or vehicle (saline) in WT mice (n = 5–6). This panel shows representative curves obtained in the dose-response analysis of mechanical allodynia caused by equimolar doses of Kyn, 3-Hk, 3-Haa in WT mice (see Supplemental Figure 8). (B) Time course of 3-Hk levels in the ipsilateral dorsal horn of the spinal cord of mice after sham (14 days) and SNI surgeries (n = 4–5 per time point). (C) Time course of Kmo mRNA expression in the ipsilateral dorsal horn of the spinal cord spinal cord after sham (14 days) and SNI surgeries. (n = 5–8). (D) Western blotting analysis of KMO expression in the ipsilateral dorsal horn of the spinal cord after sham (14 days) or SNI surgery (10 and 14 days) (n = 4–5). (E) Representative image of KMO expression analyzed by immunofluorescence in the dorsal horn of the spinal cord after sham or SNI induction (14 days). Scale bar: 50 μm. (F) Mechanical nociceptive threshold was determined before and 14 days after SNI. Mice were then treated intrathecally (i.t.) with Ro 61-8048 (KMO inhibitor; 3–300 nmol) or vehicle and mechanical allodynia was measured up to 7 hours after treatments (n = 5). (G) Mechanical nociceptive threshold was determined before and 10 days after SNI followed by intrathecal treatment with shRNA against KMO, shRNA scramble, or vehicle (indicated arrows) and mechanical allodynia was measured up to 15 days after SNI (n = 6). Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 versus sham or saline injected; ##P < 0.01, ###P < 0.001 versus mice treated with Ro 61-8048 or scramble shRNA by 2-way ANOVA with Bonferroni’s post hoc test (A, F, and G) or 1-way ANOVA with Bonferroni’s post hoc test (B–D).