Cargando…

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we...

Descripción completa

Detalles Bibliográficos
Autores principales: Defaye, Manon, Iftinca, Mircea C., Gadotti, Vinicius M., Basso, Lilian, Abdullah, Nasser S., Cuménal, Mélissa, Agosti, Francina, Hassan, Ahmed, Flynn, Robyn, Martin, Jérémy, Soubeyre, Vanessa, Poulen, Gaetan, Lonjon, Nicolas, Vachiery-Lahaye, Florence, Bauchet, Luc, Mery, Pierre Francois, Bourinet, Emmanuel, Zamponi, Gerald W., Altier, Christophe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197515/
https://www.ncbi.nlm.nih.gov/pubmed/35608912
http://dx.doi.org/10.1172/JCI154317
_version_ 1784727431382302720
author Defaye, Manon
Iftinca, Mircea C.
Gadotti, Vinicius M.
Basso, Lilian
Abdullah, Nasser S.
Cuménal, Mélissa
Agosti, Francina
Hassan, Ahmed
Flynn, Robyn
Martin, Jérémy
Soubeyre, Vanessa
Poulen, Gaetan
Lonjon, Nicolas
Vachiery-Lahaye, Florence
Bauchet, Luc
Mery, Pierre Francois
Bourinet, Emmanuel
Zamponi, Gerald W.
Altier, Christophe
author_facet Defaye, Manon
Iftinca, Mircea C.
Gadotti, Vinicius M.
Basso, Lilian
Abdullah, Nasser S.
Cuménal, Mélissa
Agosti, Francina
Hassan, Ahmed
Flynn, Robyn
Martin, Jérémy
Soubeyre, Vanessa
Poulen, Gaetan
Lonjon, Nicolas
Vachiery-Lahaye, Florence
Bauchet, Luc
Mery, Pierre Francois
Bourinet, Emmanuel
Zamponi, Gerald W.
Altier, Christophe
author_sort Defaye, Manon
collection PubMed
description The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1(+) sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non–small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions.
format Online
Article
Text
id pubmed-9197515
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher American Society for Clinical Investigation
record_format MEDLINE/PubMed
spelling pubmed-91975152022-06-22 The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain Defaye, Manon Iftinca, Mircea C. Gadotti, Vinicius M. Basso, Lilian Abdullah, Nasser S. Cuménal, Mélissa Agosti, Francina Hassan, Ahmed Flynn, Robyn Martin, Jérémy Soubeyre, Vanessa Poulen, Gaetan Lonjon, Nicolas Vachiery-Lahaye, Florence Bauchet, Luc Mery, Pierre Francois Bourinet, Emmanuel Zamponi, Gerald W. Altier, Christophe J Clin Invest Research Article The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1(+) sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non–small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions. American Society for Clinical Investigation 2022-06-15 2022-06-15 /pmc/articles/PMC9197515/ /pubmed/35608912 http://dx.doi.org/10.1172/JCI154317 Text en © 2022 Defaye et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Defaye, Manon
Iftinca, Mircea C.
Gadotti, Vinicius M.
Basso, Lilian
Abdullah, Nasser S.
Cuménal, Mélissa
Agosti, Francina
Hassan, Ahmed
Flynn, Robyn
Martin, Jérémy
Soubeyre, Vanessa
Poulen, Gaetan
Lonjon, Nicolas
Vachiery-Lahaye, Florence
Bauchet, Luc
Mery, Pierre Francois
Bourinet, Emmanuel
Zamponi, Gerald W.
Altier, Christophe
The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain
title The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain
title_full The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain
title_fullStr The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain
title_full_unstemmed The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain
title_short The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain
title_sort neuronal tyrosine kinase receptor ligand alkal2 mediates persistent pain
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197515/
https://www.ncbi.nlm.nih.gov/pubmed/35608912
http://dx.doi.org/10.1172/JCI154317
work_keys_str_mv AT defayemanon theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT iftincamirceac theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT gadottiviniciusm theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT bassolilian theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT abdullahnassers theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT cumenalmelissa theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT agostifrancina theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT hassanahmed theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT flynnrobyn theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT martinjeremy theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT soubeyrevanessa theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT poulengaetan theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT lonjonnicolas theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT vachierylahayeflorence theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT bauchetluc theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT merypierrefrancois theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT bourinetemmanuel theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT zamponigeraldw theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT altierchristophe theneuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT defayemanon neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT iftincamirceac neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT gadottiviniciusm neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT bassolilian neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT abdullahnassers neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT cumenalmelissa neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT agostifrancina neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT hassanahmed neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT flynnrobyn neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT martinjeremy neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT soubeyrevanessa neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT poulengaetan neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT lonjonnicolas neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT vachierylahayeflorence neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT bauchetluc neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT merypierrefrancois neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT bourinetemmanuel neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT zamponigeraldw neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain
AT altierchristophe neuronaltyrosinekinasereceptorligandalkal2mediatespersistentpain