The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain.


Journal

The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877

Informations de publication

Date de publication:
15 06 2022
Historique:
pubmed: 25 5 2022
medline: 18 6 2022
entrez: 24 5 2022
Statut: ppublish

Résumé

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.

Identifiants

pubmed: 35608912
pii: 154317
doi: 10.1172/JCI154317
pmc: PMC9197515
doi:
pii:

Substances chimiques

Cytokines 0
Ligands 0
Receptor Protein-Tyrosine Kinases EC 2.7.10.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : CIHR
ID : 388441
Pays : Canada

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Auteurs

Manon Defaye (M)

Department of Physiology and Pharmacology, Cumming School of Medicine.
Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine.
Alberta Children's Hospital Research Institute, and.

Mircea C Iftinca (MC)

Department of Physiology and Pharmacology, Cumming School of Medicine.
Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine.

Vinicius M Gadotti (VM)

Department of Physiology and Pharmacology, Cumming School of Medicine.
Alberta Children's Hospital Research Institute, and.
Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Lilian Basso (L)

Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM UMR1291, CNRS UMR5051, University of Toulouse III, Toulouse, France.

Nasser S Abdullah (NS)

Department of Physiology and Pharmacology, Cumming School of Medicine.
Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine.
Alberta Children's Hospital Research Institute, and.

Mélissa Cuménal (M)

Department of Physiology and Pharmacology, Cumming School of Medicine.
Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine.
Alberta Children's Hospital Research Institute, and.

Francina Agosti (F)

Department of Physiology and Pharmacology, Cumming School of Medicine.
Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine.
Alberta Children's Hospital Research Institute, and.

Ahmed Hassan (A)

Department of Physiology and Pharmacology, Cumming School of Medicine.
Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine.
Alberta Children's Hospital Research Institute, and.

Robyn Flynn (R)

Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Jérémy Martin (J)

Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM UMR1291, CNRS UMR5051, University of Toulouse III, Toulouse, France.

Vanessa Soubeyre (V)

Institute of Functional Genomics, Montpellier University, CNRS, INSERM, Montpellier, France.

Gaetan Poulen (G)

Department of Neurosurgery, Gui de Chauliac Hospital, and.

Nicolas Lonjon (N)

Department of Neurosurgery, Gui de Chauliac Hospital, and.

Florence Vachiery-Lahaye (F)

Donation and Transplantation Coordination Unit, CHU Montpellier, Montpellier University Medical Center, Montpellier, France.

Luc Bauchet (L)

Institute of Functional Genomics, Montpellier University, CNRS, INSERM, Montpellier, France.
Department of Neurosurgery, Gui de Chauliac Hospital, and.

Pierre Francois Mery (PF)

Institute of Functional Genomics, Montpellier University, CNRS, INSERM, Montpellier, France.

Emmanuel Bourinet (E)

Institute of Functional Genomics, Montpellier University, CNRS, INSERM, Montpellier, France.

Gerald W Zamponi (GW)

Department of Physiology and Pharmacology, Cumming School of Medicine.
Alberta Children's Hospital Research Institute, and.
Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Christophe Altier (C)

Department of Physiology and Pharmacology, Cumming School of Medicine.
Inflammation Research Network-Snyder Institute for Chronic Diseases, Cumming School of Medicine.
Alberta Children's Hospital Research Institute, and.

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