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 9

Astrocyte-expressed KMO maintains neuropathic pain.

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Astrocyte-expressed KMO maintains neuropathic pain. Primary cultured ast...
Primary cultured astrocytes from mouse cortex were stimulated with (A) TNF (10 ng/mL) or (B) microglia-conditioned medium (MCM). After indicated time points, mRNA was extracted and Kmo expression was analyzed by real-time PCR (n = 3–4). (C) Primary cultured astrocytes from mouse cortex or (D) differentiated U87-MG cells were stimulated with TNF (10 ng/mL) or MCM (n = 2–3). The expression of KMO in the cell extract was evaluated 24 hours after stimulation by Western blotting. (E) Schematic of the astrocyte-specific shRNA lentiviral vector (LV) used to knock down KMO in astrocytes of the spinal cord. (F) Mechanical nociceptive threshold was determined before and 9 days after SNI followed by intrathecal treatment with lentiviral vectors expressing shRNA control or shRNA Kmo (n = 4–5) on days 10 and 13 after SNI. (G) Mechanical allodynia was measured up to 16 days after SNI and ipsilateral dorsal horn of the spinal cord was collected for analyses of KMO expression (n = 4). Data are expressed as mean ± SEM. *P < 0.05 versus medium treated; #P < 0.05 versus mice treated with scramble shRNA by 1-way ANOVA with Bonferroni’s post hoc test (A–C and G) or 2-way ANOVA with Bonferroni’s post hoc test (F).