Details
| Original language | English |
|---|---|
| Article number | 226 |
| Journal | Cell communication and signaling |
| Volume | 23 |
| Issue number | 1 |
| Publication status | Published - 16 May 2025 |
Abstract
In respiratory airway epithelial cells, lipopolysaccharide (LPS) treatment induced an enhancement of connexin 26 (Cx26) hemichannel activity shown by dye uptake experiments after siRNA-mediated knock-down of Cx26. This effect was already observed at infection relevant concentrations (≤ 10 ng/mL LPS) and involved tumor necrosis factor alpha (TNF-α)- and Ca2+-dependent signaling. High concentrations (1 µg/mL LPS) reduced the transepithelial electrical resistance (TEER) of Calu-3 cells by 35% within an application time of 3 h followed by a recovery. Parallel to barrier alteration, a reduced tight junction organization rate (TiJOR) of claudin-4 (CLDN4) by 75% was observed within an application time of 3 h. After TEER recovery, CLDN4 TiJOR stayed reduced. Low concentrations (10 ng/mL LPS) required three times repeated application for barrier reduction and CLDN4 TiJOR reduction by 30%. The small molecule CVB4-57, newly published as a potential inhibitor of Cx26 hemichannels, mitigated the effects of LPS on the epithelial barrier function. Molecular docking studies revealed a potential interaction between CVB4-57 and Cx26 thereby reducing its hemichannel activity. We conclude that LPS-related enhancement of Cx26 hemichannel activity acts like a “molecular scar” that weakens the lung epithelium, which could be attenuated by agents targeting Cx26 hemichannels.
Keywords
- Airway epithelium, Barrier function, Calu-3 cells, Connexin channels; lipopolysaccharide, Cytokine, PCLS, Primary cells
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology
Cite this
- Standard
- Harvard
- Apa
- Vancouver
- BibTeX
- RIS
In: Cell communication and signaling, Vol. 23, No. 1, 226, 16.05.2025.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Repression of Connexin26 hemichannel activity protects the barrier function of respiratory airway epithelial cells against LPS-induced alteration
AU - Lehrich, Tina
AU - Dierks, Anne
AU - Plenge, Masina
AU - Obernolte, Helena
AU - Grieger, Klaudia
AU - Sewald, Katherina
AU - Rodriguez, Frederic
AU - Malet, Lucie
AU - Braubach, Peter
AU - Bedos-Belval, Florence
AU - Ngezahayo, Anaclet
N1 - Publisher Copyright: © The Author(s) 2025.
PY - 2025/5/16
Y1 - 2025/5/16
N2 - In respiratory airway epithelial cells, lipopolysaccharide (LPS) treatment induced an enhancement of connexin 26 (Cx26) hemichannel activity shown by dye uptake experiments after siRNA-mediated knock-down of Cx26. This effect was already observed at infection relevant concentrations (≤ 10 ng/mL LPS) and involved tumor necrosis factor alpha (TNF-α)- and Ca2+-dependent signaling. High concentrations (1 µg/mL LPS) reduced the transepithelial electrical resistance (TEER) of Calu-3 cells by 35% within an application time of 3 h followed by a recovery. Parallel to barrier alteration, a reduced tight junction organization rate (TiJOR) of claudin-4 (CLDN4) by 75% was observed within an application time of 3 h. After TEER recovery, CLDN4 TiJOR stayed reduced. Low concentrations (10 ng/mL LPS) required three times repeated application for barrier reduction and CLDN4 TiJOR reduction by 30%. The small molecule CVB4-57, newly published as a potential inhibitor of Cx26 hemichannels, mitigated the effects of LPS on the epithelial barrier function. Molecular docking studies revealed a potential interaction between CVB4-57 and Cx26 thereby reducing its hemichannel activity. We conclude that LPS-related enhancement of Cx26 hemichannel activity acts like a “molecular scar” that weakens the lung epithelium, which could be attenuated by agents targeting Cx26 hemichannels.
AB - In respiratory airway epithelial cells, lipopolysaccharide (LPS) treatment induced an enhancement of connexin 26 (Cx26) hemichannel activity shown by dye uptake experiments after siRNA-mediated knock-down of Cx26. This effect was already observed at infection relevant concentrations (≤ 10 ng/mL LPS) and involved tumor necrosis factor alpha (TNF-α)- and Ca2+-dependent signaling. High concentrations (1 µg/mL LPS) reduced the transepithelial electrical resistance (TEER) of Calu-3 cells by 35% within an application time of 3 h followed by a recovery. Parallel to barrier alteration, a reduced tight junction organization rate (TiJOR) of claudin-4 (CLDN4) by 75% was observed within an application time of 3 h. After TEER recovery, CLDN4 TiJOR stayed reduced. Low concentrations (10 ng/mL LPS) required three times repeated application for barrier reduction and CLDN4 TiJOR reduction by 30%. The small molecule CVB4-57, newly published as a potential inhibitor of Cx26 hemichannels, mitigated the effects of LPS on the epithelial barrier function. Molecular docking studies revealed a potential interaction between CVB4-57 and Cx26 thereby reducing its hemichannel activity. We conclude that LPS-related enhancement of Cx26 hemichannel activity acts like a “molecular scar” that weakens the lung epithelium, which could be attenuated by agents targeting Cx26 hemichannels.
KW - Airway epithelium
KW - Barrier function
KW - Calu-3 cells
KW - Connexin channels; lipopolysaccharide
KW - Cytokine
KW - PCLS
KW - Primary cells
UR - http://www.scopus.com/inward/record.url?scp=105005459837&partnerID=8YFLogxK
U2 - 10.1186/s12964-025-02228-6
DO - 10.1186/s12964-025-02228-6
M3 - Article
C2 - 40380298
AN - SCOPUS:105005459837
VL - 23
JO - Cell communication and signaling
JF - Cell communication and signaling
SN - 1478-811X
IS - 1
M1 - 226
ER -