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