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The NOD2 signaling in peripheral macrophages contributes to neuropathic pain development

Santa-Cecília, Flávia V.a; Ferreira, David W.a; Guimaraes, Rafaela M.a; Cecilio, Nerry T.a; Fonseca, Miriam M.a; Lopes, Alexandre H.a; Davoli-Ferreira, Marcelaa; Kusuda, Ricardoa; Souza, Guilherme R.a; Nachbur, Uelib,c; Alves-Filho, José C.a; Teixeira, Mauro M.d; Zamboni, Dario S.e; Cunha, Fernando Q.a; Cunha, Thiago M.a,*

doi: 10.1097/j.pain.0000000000001383
Research Paper
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Neuropathic pain is one of the most important types of chronic pain. It is caused by neuronal damage. Clinical and experimental studies suggest a critical role for neuroimmune interactions in the development of neuropathic pain. In this article, we have shown that the cytoplasmic receptor Nod-like receptor-2, NOD2, and its adaptor-signaling molecule RIPK2 participate in the development of neuropathic pain after peripheral nerve injury (spared nerve injury model). The activation of NOD2 signaling in peripheral macrophage mediates the development of neuropathic pain through the production of pronociceptive cytokines (tumor necrosis factor and IL-1β). This study found that peripheral nerve injury promoted a systemic increase in the NOD2 ligand. These results highlight a previously undetermined role for NOD2 signaling in the development of neuropathic pain, suggesting a new potential target for preventing neuropathic pain.

In this study, we have shown the role of NOD2 signaling in peripheral macrophage for the development of neuropathic pain.

aCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil

bThe Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

cDepartment of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia

dLaboratorio de Imunofarmacologia, Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

eDepartment of Cellular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil

Corresponding author. Address: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, São Paulo, Brazil. Tel.: +55 16 3602-0199; fax: +55 16 3633-2301. E-mail address: thicunha@fmrp.usp.br (T.M. Chuna).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

F.V. Santa-Cecília and D.W. Ferreira are co-first authors.

Received November 13, 2017

Accepted August 17, 2018

© 2019 International Association for the Study of Pain
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