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Wang, Y.* ; Wang, X.* ; Qi, R.* ; Lu, Y.* ; Tao, Y.* ; Jiang, D. ; Sun, Y.* ; Jiang, X.* ; Liu, C.* ; Zhang, Y.* ; Tao, J.*

Interleukin 33-mediated inhibition of A-type K+ channels induces sensory neuronal hyperexcitability and nociceptive behaviors in mice.

Theranostics 12, 2232-2247 (2022)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
Background: Interleukin-33 (IL-33) has been implicated in nociceptive pain behaviors. However, the underlying molecular and cellular mechanisms remain unclear. Methods: Using electrophysiological recording, immunoblot analysis, immunofluorescence labeling, reverse transcription-PCR, siRNA-mediated knockdown approach and behavior tests, we determined the role of IL-33 in regulating sensory neuronal excitability and pain sensitivity mediated by A-type K+ channels. Results: IL-33 decreased A-type transient outward K+ currents (IA) in small-sized DRG neurons in a concentration-dependent manner, whereas the delayed rectifier currents (IDR) remained unaffected. This IL-33-induced IA decrease was dependent on suppression of the tumorigenicity 2 (ST2) receptor and was associated with a hyperpolarizing shift in the steady-state inactivation. Antagonism of Syk abrogated the IL-33-induced IA response, while inhibition of JAK2 and PKA elicited no such effect. Exposure of DRG cells to IL-33 increased the activity of Akt, but surprisingly, neither Akt nor PI3K influenced the IL-33-induced IA response. IL-33 increased the level of phosphorylated p38 mitogen-activated protein kinase (MAPK). Chemical inhibition of p38 and genetic siRNA knockdown of p38 beta (p38β), but not p38α, abrogated the IA response induced by IL-33. Moreover, IL-33 increased neuronal excitability of DRG neurons and facilitated peripheral pain sensitivity in mice; both of these effects were occluded by IA blockade. Conclusions: Our present study reveals a novel mechanism by which IL-33/ST2 suppresses IA via a Syk-dependent p38β signaling pathway. This mechanism thereby increases DRG neuronal excitability and pain sensitivity in mice. Targeting IL-33/ST2-mediated p38β signaling may represent a therapeutic approach to ameliorate pain behaviors.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter A-type K+ Channel ; Dorsal Root Ganglion Neurons ; Interleukin 33 ; Pain; Kv4.2 Potassium Channel; Beta-gamma-subunits; Protein-kinase-a; Phosphatidylinositol 3-kinase; Signaling Contributes; Receptor Stimulation; Neuropathic Pain; Hyperalgesia; Modulation; Pathway
e-ISSN 1838-7640
Zeitschrift Theranostics
Quellenangaben Band: 12, Heft: 5, Seiten: 2232-2247 Artikelnummer: , Supplement: ,
Verlag Ivyspring
Verlagsort Po Box 4546, Lake Haven, Nsw 2263, Australia
Begutachtungsstatus Peer reviewed
Förderungen Priority Academic Program Development of Jiangsu Higher Education Institutions
Natural Science Foundation of Colleges and Universities in Jiangsu Province
Natural Science Foundation of Jiangsu Province
Science and Technology Bureau of Suzhou
Jiangsu Key Laboratory of Neuropsychiatric Diseases
National Natural Science Foundation of China