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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-06-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI154317 |
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| author | Manon Defaye Mircea C. Iftinca Vinicius M. Gadotti Lilian Basso Nasser S. Abdullah Mélissa Cuménal Francina Agosti Ahmed Hassan Robyn Flynn Jérémy Martin Vanessa Soubeyre Gaetan Poulen Nicolas Lonjon Florence Vachiery-Lahaye Luc Bauchet Pierre Francois Mery Emmanuel Bourinet Gerald W. Zamponi Christophe Altier |
| author_facet | Manon Defaye Mircea C. Iftinca Vinicius M. Gadotti Lilian Basso Nasser S. Abdullah Mélissa Cuménal Francina Agosti Ahmed Hassan Robyn Flynn Jérémy Martin Vanessa Soubeyre Gaetan Poulen Nicolas Lonjon Florence Vachiery-Lahaye Luc Bauchet Pierre Francois Mery Emmanuel Bourinet Gerald W. Zamponi Christophe Altier |
| author_sort | Manon Defaye |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T15:41:01Z |
| format | Article |
| id | doaj.art-a6e3c5ad613d48638247c916de48a347 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-13T15:41:01Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-a6e3c5ad613d48638247c916de48a3472022-12-22T02:41:08ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-06-0113212The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent painManon DefayeMircea C. IftincaVinicius M. GadottiLilian BassoNasser S. AbdullahMélissa CuménalFrancina AgostiAhmed HassanRobyn FlynnJérémy MartinVanessa SoubeyreGaetan PoulenNicolas LonjonFlorence Vachiery-LahayeLuc BauchetPierre Francois MeryEmmanuel BourinetGerald W. ZamponiChristophe AltierThe 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.https://doi.org/10.1172/JCI154317Neuroscience |
| spellingShingle | Manon Defaye Mircea C. Iftinca Vinicius M. Gadotti Lilian Basso Nasser S. Abdullah Mélissa Cuménal Francina Agosti Ahmed Hassan Robyn Flynn Jérémy Martin Vanessa Soubeyre Gaetan Poulen Nicolas Lonjon Florence Vachiery-Lahaye Luc Bauchet Pierre Francois Mery Emmanuel Bourinet Gerald W. Zamponi Christophe Altier The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain The Journal of Clinical Investigation Neuroscience |
| 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 | Neuroscience |
| url | https://doi.org/10.1172/JCI154317 |
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