Myelin barrier breakdown, mechanical hypersensitivity, and painfulness in polyneuropathy with claudin-12 deficiency.

Autor: Chen JT; University Hospital Würzburg, Center for Interdisciplinary Pain Medicine, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany., Hu X; University Hospital Würzburg, Center for Interdisciplinary Pain Medicine, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany., Otto IUC; University Hospital Würzburg, Center for Interdisciplinary Pain Medicine, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany., Schürger C; University Hospital Würzburg, Center for Interdisciplinary Pain Medicine, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany., von Bieberstein BR; University Hospital Würzburg, Center for Interdisciplinary Pain Medicine, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany., Doppler K; University Hospital Würzburg, Department of Neurology, 97080 Würzburg, Germany., Krug SM; Charité-Universitätsmedizin Berlin, Clinical Physiology/Nutritional Medicine, 13125 Berlin, Germany., Hankir MK; University Hospital Würzburg, Department of General, Transplantation, Visceral, Vascular and Pediatric Surgery, 97080 Würzburg, Germany., Blasig R; Leibnitz Institute of Molecular Pharmacology, Departments of Molecular Physiology and Cell Biology, 13125 Berlin, Germany., Sommer C; University Hospital Würzburg, Department of Neurology, 97080 Würzburg, Germany., Brack A; University Hospital Würzburg, Center for Interdisciplinary Pain Medicine, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany., Blasig IE; Leibnitz Institute of Molecular Pharmacology, Departments of Molecular Physiology and Cell Biology, 13125 Berlin, Germany., Rittner HL; University Hospital Würzburg, Center for Interdisciplinary Pain Medicine, Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, 97080 Würzburg, Germany. Electronic address: rittner_h@ukw.de.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2023 Sep; Vol. 185, pp. 106246. Date of Electronic Publication: 2023 Jul 30.
DOI: 10.1016/j.nbd.2023.106246
Abstrakt: Background: The blood-nerve and myelin barrier shield peripheral neurons and their axons. These barriers are sealed by tight junction proteins, which control the passage of potentially noxious molecules including proinflammatory cytokines via paracellular pathways. Peripheral nerve barrier breakdown occurs in various neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and traumatic neuropathy. Here, we studied the functional role of the tight junction protein claudin-12 in regulating peripheral nerve barrier integrity and CIDP pathogenesis.
Methods: Sections from sural nerve biopsies from 23 patients with CIDP and non-inflammatory idiopathic polyneuropathy (PNP) were analyzed for claudin-12 and -19 immunoreactivity. Cldn12-KO mice were generated and subjected to the chronic constriction injury (CCI) model of neuropathy. These mice were then characterized using a battery of barrier and behavioral tests, histology, immunohistochemistry, and mRNA/protein expression. In phenotype rescue experiments, the proinflammatory cytokine TNFα was neutralized with the anti-TNFα antibody etanercept; the peripheral nerve barrier was stabilized with the sonic hedgehog agonist smoothened (SAG).
Results: Compared to those without pain, patients with painful neuropathy exhibited reduced claudin-12 expression independently of fiber loss. Accordingly, global Cldn12-KO in male mice, but not fertile female mice, selectively caused mechanical allodynia associated with a leaky myelin barrier, increased TNFα, decreased sonic hedgehog (SHH), and loss of small axons accompanied by reduced peripheral myelin protein 22 (Pmp22). Other barriers and neurological functions remained intact. The Cldn12-KO phenotype could be rescued either by neutralizing TNFα with etanercept or stabilizing the barrier with SAG, which both also upregulated the Schwann cell barrier proteins Cldn19 and Pmp22.
Conclusion: These results point to a critical role for claudin-12 in maintaining the myelin barrier presumably via Pmp22 and highlight restoration of the hedgehog pathway as a potential treatment strategy for painful inflammatory neuropathy.
Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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