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Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice

Peripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve...

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Autores principales: Rivat, Cyril, Sar, Chamroeun, Mechaly, Ilana, Leyris, Jean-Philippe, Diouloufet, Lucie, Sonrier, Corinne, Philipson, Yann, Lucas, Olivier, Mallié, Sylvie, Jouvenel, Antoine, Tassou, Adrien, Haton, Henri, Venteo, Stéphanie, Pin, Jean-Philippe, Trinquet, Eric, Charrier-Savournin, Fabienne, Mezghrani, Alexandre, Joly, Willy, Mion, Julie, Schmitt, Martine, Pattyn, Alexandre, Marmigère, Frédéric, Sokoloff, Pierre, Carroll, Patrick, Rognan, Didier, Valmier, Jean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847526/
https://www.ncbi.nlm.nih.gov/pubmed/29531216
http://dx.doi.org/10.1038/s41467-018-03496-2
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author Rivat, Cyril
Sar, Chamroeun
Mechaly, Ilana
Leyris, Jean-Philippe
Diouloufet, Lucie
Sonrier, Corinne
Philipson, Yann
Lucas, Olivier
Mallié, Sylvie
Jouvenel, Antoine
Tassou, Adrien
Haton, Henri
Venteo, Stéphanie
Pin, Jean-Philippe
Trinquet, Eric
Charrier-Savournin, Fabienne
Mezghrani, Alexandre
Joly, Willy
Mion, Julie
Schmitt, Martine
Pattyn, Alexandre
Marmigère, Frédéric
Sokoloff, Pierre
Carroll, Patrick
Rognan, Didier
Valmier, Jean
author_facet Rivat, Cyril
Sar, Chamroeun
Mechaly, Ilana
Leyris, Jean-Philippe
Diouloufet, Lucie
Sonrier, Corinne
Philipson, Yann
Lucas, Olivier
Mallié, Sylvie
Jouvenel, Antoine
Tassou, Adrien
Haton, Henri
Venteo, Stéphanie
Pin, Jean-Philippe
Trinquet, Eric
Charrier-Savournin, Fabienne
Mezghrani, Alexandre
Joly, Willy
Mion, Julie
Schmitt, Martine
Pattyn, Alexandre
Marmigère, Frédéric
Sokoloff, Pierre
Carroll, Patrick
Rognan, Didier
Valmier, Jean
author_sort Rivat, Cyril
collection PubMed
description Peripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve injury site express the cytokine FL, the ligand of fms-like tyrosine kinase 3 receptor (FLT3). FLT3 activation by intra-sciatic nerve injection of FL is sufficient to produce pain hypersensitivity, activate PNP-associated gene expression and generate short-term and long-term sensitization of sensory neurons. Nerve injury-induced PNP symptoms and associated-molecular changes were strongly altered in Flt3-deficient mice or reversed after neuronal FLT3 downregulation in wild-type mice. A first-in-class FLT3 negative allosteric modulator, discovered by structure-based in silico screening, strongly reduced nerve injury-induced sensory hypersensitivity, but had no effect on nociception in non-injured animals. Collectively, our data suggest a new and specific therapeutic approach for PNP.
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spelling pubmed-58475262018-03-15 Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice Rivat, Cyril Sar, Chamroeun Mechaly, Ilana Leyris, Jean-Philippe Diouloufet, Lucie Sonrier, Corinne Philipson, Yann Lucas, Olivier Mallié, Sylvie Jouvenel, Antoine Tassou, Adrien Haton, Henri Venteo, Stéphanie Pin, Jean-Philippe Trinquet, Eric Charrier-Savournin, Fabienne Mezghrani, Alexandre Joly, Willy Mion, Julie Schmitt, Martine Pattyn, Alexandre Marmigère, Frédéric Sokoloff, Pierre Carroll, Patrick Rognan, Didier Valmier, Jean Nat Commun Article Peripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve injury site express the cytokine FL, the ligand of fms-like tyrosine kinase 3 receptor (FLT3). FLT3 activation by intra-sciatic nerve injection of FL is sufficient to produce pain hypersensitivity, activate PNP-associated gene expression and generate short-term and long-term sensitization of sensory neurons. Nerve injury-induced PNP symptoms and associated-molecular changes were strongly altered in Flt3-deficient mice or reversed after neuronal FLT3 downregulation in wild-type mice. A first-in-class FLT3 negative allosteric modulator, discovered by structure-based in silico screening, strongly reduced nerve injury-induced sensory hypersensitivity, but had no effect on nociception in non-injured animals. Collectively, our data suggest a new and specific therapeutic approach for PNP. Nature Publishing Group UK 2018-03-12 /pmc/articles/PMC5847526/ /pubmed/29531216 http://dx.doi.org/10.1038/s41467-018-03496-2 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Rivat, Cyril
Sar, Chamroeun
Mechaly, Ilana
Leyris, Jean-Philippe
Diouloufet, Lucie
Sonrier, Corinne
Philipson, Yann
Lucas, Olivier
Mallié, Sylvie
Jouvenel, Antoine
Tassou, Adrien
Haton, Henri
Venteo, Stéphanie
Pin, Jean-Philippe
Trinquet, Eric
Charrier-Savournin, Fabienne
Mezghrani, Alexandre
Joly, Willy
Mion, Julie
Schmitt, Martine
Pattyn, Alexandre
Marmigère, Frédéric
Sokoloff, Pierre
Carroll, Patrick
Rognan, Didier
Valmier, Jean
Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
title Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
title_full Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
title_fullStr Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
title_full_unstemmed Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
title_short Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
title_sort inhibition of neuronal flt3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847526/
https://www.ncbi.nlm.nih.gov/pubmed/29531216
http://dx.doi.org/10.1038/s41467-018-03496-2
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