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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 Article has an altmetric score of 114

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

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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 2

IDO1 is involved in the maintenance of neuropathic pain but has no role in nociceptive or inflammatory pain.

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IDO1 is involved in the maintenance of neuropathic pain but has no role ...
(A) Mechanical and (B) cold nociceptive responses were evaluated before and up to 28 days after SNI and sham surgeries in WT and Ido1–/– mice. (n = 5–9). (C and D) Mechanical nociceptive threshold was determined before and 14 days after SNI. Mice were treated intraperitoneally (i.p.) with vehicle or 1-methyl-DL-tryptophan (1-MT, 0.03–3 mg/mouse) or norharmane (nor, 0.2–20 mg/kg), and mechanical allodynia was measured up to 24 hours after treatment (n = 5). (E) The nociceptive thermal threshold was tested in naive WT and Ido1–/– mice at 48°C, 52°C, and 56°C using the hot-plate test (n = 8). (F) Formalin (1%) was used to produce overt pain-like behavior. Total duration (seconds) of nociceptive behaviors for 0 to 10 minutes (1st phase) and for 10 to 50 minutes (2nd phase) after formalin injection was evaluated in WT and Ido1–/– mice (n = 7). (G) Mechanical nociceptive threshold using von Frey test (n = 4–5) was evaluated in WT and Ido1–/– mice followed by intraplantar injection of carrageenan (Cg, 100 μg per paw) or vehicle (saline). (H and I) Mechanical and thermal (heat) nociceptive threshold using von Frey test (n = 7) and Hargreaves’ test, respectively, were evaluated in WT and Ido1–/– mice followed by intraplantar injection of CFA (10 μL per paw). Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 versus sham or vehicle; #P < 0.05, ###P < 0.001 versus Ido1–/– mice by 2-way ANOVA with Bonferroni’s post hoc test (A–D and G–I) or unpaired, 2-tailed Student’s t test (E and F). NS, no statistical significance.

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